WO2009061411A2 - Use melanocortins to treat insulin sensitivity - Google Patents

Use melanocortins to treat insulin sensitivity Download PDF

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Publication number
WO2009061411A2
WO2009061411A2 PCT/US2008/012490 US2008012490W WO2009061411A2 WO 2009061411 A2 WO2009061411 A2 WO 2009061411A2 US 2008012490 W US2008012490 W US 2008012490W WO 2009061411 A2 WO2009061411 A2 WO 2009061411A2
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WO
WIPO (PCT)
Prior art keywords
arg
cys
seq
ala
trp
Prior art date
Application number
PCT/US2008/012490
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French (fr)
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WO2009061411A3 (en
Inventor
Heather A. Halem
Michael Dewitt Culler
Andrew A. Butler
Original Assignee
Ipsen Pharma S.A.S.
Board Of Supervisors Of Louisiana State University And Agriculture And Mechanical College
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority to KR1020137011647A priority Critical patent/KR101662044B1/en
Priority to BRPI0819188-3A priority patent/BRPI0819188B1/en
Priority to KR1020147036380A priority patent/KR20150013339A/en
Priority to JP2010532076A priority patent/JP2011502987A/en
Priority to DK08846334.4T priority patent/DK2214693T3/en
Priority to EP15179111.8A priority patent/EP2979703B1/en
Priority to CN2008801238931A priority patent/CN101980717A/en
Priority to PL08846334T priority patent/PL2214693T3/en
Priority to KR1020107012327A priority patent/KR101290623B1/en
Priority to NZ585131A priority patent/NZ585131A/en
Priority to ES08846334.4T priority patent/ES2555522T3/en
Priority to EP08846334.4A priority patent/EP2214693B1/en
Application filed by Ipsen Pharma S.A.S., Board Of Supervisors Of Louisiana State University And Agriculture And Mechanical College filed Critical Ipsen Pharma S.A.S.
Priority to CA2704651A priority patent/CA2704651C/en
Priority to AU2008325194A priority patent/AU2008325194B2/en
Priority to US12/740,917 priority patent/US9155777B2/en
Publication of WO2009061411A2 publication Critical patent/WO2009061411A2/en
Publication of WO2009061411A3 publication Critical patent/WO2009061411A3/en
Priority to IL205554A priority patent/IL205554A/en
Priority to HK11100510.8A priority patent/HK1146242A1/en
Priority to US14/844,128 priority patent/US9439943B2/en
Priority to US15/242,866 priority patent/US9827286B2/en
Priority to IL249998A priority patent/IL249998B/en
Priority to US15/801,432 priority patent/US20180303899A1/en
Priority to US16/225,189 priority patent/US20190111105A1/en
Priority to US17/831,887 priority patent/US20220339239A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links

Definitions

  • POMC pro-hormone pro-opiomelanocortin
  • melanocortin receptors Five melanocortin receptors (MC-R) have been characterized to date. These include melanocyte-specific receptor (MCl-R), corticoadrenal-specific ACTH receptor (MC2-R), melacortin-3 (MC3-R), melanocortin-4 (MC4-R) and melanocortin-
  • M5-R melanocortin 5 receptor
  • MC-R melanocortin
  • Complications of body weight disorders commonly include an inability to produce and utilize insulin, often resulting in faulty glucose regulation.
  • the consequence of failure to properly control glucose metabolism affects many aspects of overall health including energy metabolism, neuropathy and heart disease.
  • Current progress with receptor-selective melanocortin receptor ligands evidences the therapeutic potential of melanocortin receptor activation, particularly MC4-R, in the treatment of glucose regulation, including insulin metabolism.
  • the present invention is directed to the use of peptides which are ligands of one or more of the melanocortin receptors (MC-R), or the pharmaceutically- acceptable salts thereof, to treat mammals suffering from insulin resistance.
  • the ligands are agonists to the melanocortin 4 receptor.
  • the melanocortin receptor ligands are according to the formulae described herein or are selected from particular peptides described herein.
  • the insulin resistant subject mammals may be obese or overweight and may lose weight as a result of the administration of the peptides of the invention.
  • the insulin resistant subject mammals may also be normal weight or lean.
  • the insulin resistant condition of the subject mammals may be treated independent of weight loss.
  • the subject mammals may be human subjects of any age, such as an infant, a child, an adult or an elderly adult.
  • the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor 4 ligand according to Formula (I) and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof (see International Patent Application Publication Number WO 2007/008704, incorporated herein by reference in its entirety): (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1
  • a 1 is Ace, HN-(CH2)m-C(O), L- or D-amino acid, or deleted;
  • a 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or GIu;
  • a 3 is GIy, Ala, /?-Ala, Gaba, Aib, D-amino acid, or deleted;
  • a 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X ⁇ X 2 ,X*,X ⁇ X ⁇ he;
  • a 5 is D-Phe, D-I-NaI, D-2-Nal, D-Trp, D-BaI, D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe or D-(Et)Tyr;
  • a 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH 2 )n-N(R 4 R 5 ))-C(O);
  • a 7 is Trp, 1-Nal, 2-Nal, BaI, Bip, D-Trp, D-I-NaI, D-2-Nal, D-BaI or D-Bip;
  • a 8 is GIy, D-AIa, Ace, Ala, ⁇ -Ala, Gaba, Apn, Ahx, Aha, HN-(CH 2 ) S -C(O), or deleted;
  • a 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys;
  • a 10 is Ace, HN-(CH2)t-C(O), L- or D-amino acid, or deleted;
  • R 1 is OH or NH 2 ; each of R 2 and R 3 is, independently for each occurrence, selected from the group consisting of H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (Ci-C3o)acyl, (C 2 -C3o)alkenyl, (0-C3o)alkynyl, aryl(Ci-C3o)alkyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (Ci-C3o)acyl, substituted (C2-C3o)alkenyl, substituted (C 2 -C3o)alkynyl, substituted aryl(Ci-C3o)alkyl, and substituted aryl(Ci-
  • each of R 4 and R 5 is, independently for each occurrence, H, (Ci-G ⁇ o)alkyl, (G-
  • X 1 , X 2 , X 3 , X 4 , and X 5 each is, independently for each occurrence, H, F, Cl, Br, I, (Ci-io)alkyl, substituted (Ci-io)alkyl, (C2-io)alkenyl, substituted (C 2 -io)alkenyl,
  • R 4 is (Ci-C4o)acyl, aryl(Ci-G»o)acyl, substituted (Ci-C4o)acyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl, or -C(NH)-NH 2
  • R 5 is H or (Ci-C4o)alkyl, (Ci-C4o)heteroalkyl, (Cz-C4o)alkenyl, (C 2 -C « > )alkynyl, aryl(Ci- C4o)alkyl, substituted (Ci-C4o)alkyl, substituted (Ci- C4o)heteroalkyl, substituted (C2-C4o)alkenyl, substituted (C2-C4o)alkynyl, or substituted aryl(G-C4o)alkyl;
  • R 3 is H, (Ci-Qo)alkyl, (Ci-C3o)heteroalkyl, (C2-C3o)alkenyl, (Cz-Csojalkynyl, aryl(Ci-C3o)alkyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)
  • the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a subgroup of melanocortin receptor ligands of the immediate foregoing Formula I, wherein':
  • a 1 is A6c, Arg, D-Arg, Cha, D-Cha, hCha, Chg, D-Chg, Gaba, He, Leu, hLeu, Met, jS-hMet, 2-Nal, D-2-Nal, Nip, NIe, Oic, Phe, D-Phe, hPhe, hPro, VaI, or deleted;
  • a 2 is Asp, Cys, D-Cys, hCys, D-hCys, GIu, Pen, or D-Pen;
  • a 3 is D- Abu, Aib, Ala, /-Ala, D-AIa, D-Cha, Gaba, D-GIu, GIy, D-IIe, D-Leu,
  • a 4 is His or 3-Pal;
  • a 5 is D-BaI, D-I-NaI, D-2-Nal, D-Phe, D-Trp, or D-(Et)Tyr;
  • a 6 is Arg, or hArg
  • a 7 is BaI, Bip, 1-Nal, 2-Nal, Trp, D-Trp;
  • a 8 is A6c, D-AIa, Aha, Ahx, Ala, /-Ala, Apn, Gaba, GIy or deleted;
  • a 9 is Cys, D-Cys, hCys, D-hCys, Lys, Pen, or D-Pen;
  • a 10 is Thr, or deleted; wherein at least one of A 3 or A 8 is deleted, but not both, or pharmaceutically acceptable salts thereof.
  • More preferred compounds of the immediately foregoing group of ligands according to Formula (I) useful to treat insulin resistance in a mammalian subject, with or without weight loss, are compounds of the formula:
  • the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor ligand according to Formula (II) and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof (see International Patent Application Publication Number WO 2007/008704 incorporated herein by reference in its entirety):
  • a 1 is NIe or deleted
  • a 2 is Cys or Asp
  • a 3 is GIu or D-AIa;
  • a 4 is His;
  • a 5 is D-Phe
  • a 6 is Arg
  • a 7 is Trp, 2-Nal or BaI
  • a 8 is GIy, Ala, D-AIa, ⁇ -Ala, Gaba or Apn;
  • a 9 is Cys or Lys; each of R 2 and R 3 is independently selected from the group consisting of H or provided that
  • More preferred of the immediately foregoing group of compounds which are useful to treat insulin resistance in a mammalian subject, with or without weight loss, are compounds of the formula: Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH 2 ; SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH2; SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp- ⁇ - AIa-CyS)-NH 2 ; SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D-
  • the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor compound according to Formula (III), and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof (see International Application Publication Number WO 2007/008684, incorporated herein by reference in its entirety): (R 2 R 3 )-B'-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -A 11 -A 12 -A 13 -B 2 -B 3 -R 1
  • B 1 is a peptide moiety which contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ,or 15 amino acids, wherein at least 5 amino acids are independently selected from the group consisting of L-Arg, D-Arg, L-hArg and D-hArg, or B 1 is optionally deleted;
  • a 1 is Ace, HN-(CH 2 )m-C(O), L- or D-amino acid or deleted;
  • a 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or GIu;
  • a 3 is GIy, GIu, Ala,/?-Ala, Gaba, Aib, D-amino acid or deleted;
  • a 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe;
  • a 5 is D-Phe, D-I-NaI, D-2-Nal, D-Trp, D-BaI, D-(X',X 2 ,X 3 ,X 4 ,X 5 )Phe, D-(Et)Tyr, D-Dip, D-Bip or D-Bpa ;
  • a 6 is Arg, hArg, Dab, Dap, Lys, Orn or HN-CH((CH 2 )n-N(R 4 R 5 ))-C(O);
  • a 7 is Trp, 1-NaI, 2-Nal, BaI, Bip, Dip, Bpa, D-Trp, D-I-NaI, D-2-Nal, D-BaI, D- Bip, D-Dip or D-Bpa;
  • a 8 is GIy, D-AIa, Ace, Ala, ⁇ -AIa, Gaba, Apn, Ahx, Aha, HN-(CH 2 )s-C(O) or deleted;
  • a 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn or Lys;
  • a 10 is Ace, HN-(CH 2 )I-C(O), Pro, hPro, 3-Hyp, 4-Hyp, Thr, an L- or D-amino acid or deleted;
  • a 11 is Pro, hPro, 3-Hyp, 4-Hyp or deleted;
  • a 12 is Lys, Dab, Dap, Arg, hArg or deleted;
  • a 13 is Asp, GIu or deleted;
  • B 2 is a peptide moiety containing 1, 2, 3, 4, or 5 amino acids or deleted
  • B 3 is a peptide moiety which contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids wherein at least 5 amino acids are independently selected from the group consisting of L-Arg, D-Arg, L-hArg and D-hArg, or is deleted;
  • R 1 is OH or NH 2 ;
  • R 2 and R 3 each is , independently for each occurrence, selected from the group consisting of H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (Ci-C3o)acyl, (C2-C3o)alkenyl, (G- C3o)alkynyl, aryl(Ci-C3o)alkyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (Ci-C3o)acyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl, substituted aryl(G-C3o)alkyl and substituted aryl(G-C3o)acyl; R 4 and R 5 each is, independently for each occurrence, H, (Ci-C
  • X 1 , X 2 , X 3 , X 4 and X 5 each is, independently for each occurrence, H, F, Cl, Br, I, (Ci-io)alkyl, substituted (G-io)alkyl, (C2-io)alkenyl, substituted (G-io)alkenyl, (G- io)alkynyl, substituted (G-io)alkynyl, aryl, substituted aryl, OH, NH2, NO2 or CN; provided that:
  • R 4 when R 4 is (Ci-C4o)acyl, aryl(G-C4o)acyl, substituted (Ci-C4o)acyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl or C(NH)-NH 2 , then R 5 is H, (G- Go)alkyl, (G-Go)heteroalkyl, (G-C ⁇ lkenyl, (G-Go)alkynyl, aryl(G-Go)alkyl, substituted (G-Go)aLkyl, substituted (G-Go)heteroalkyl, substituted (C 2 -C4o)alkenyl, substituted (G-Go)alkynyl or substituted aryl(G-Cio)alkyl;
  • R 2 is (G-Go)acyl, aryl(G-C3o)acyl, substituted (G-C3o)acyl or substituted aryl(G-C3o)acyl
  • R 3 is H, (G-Qo)alkyl, (G-C3o)heteroalkyl, (G- C3o)alkenyl, (G-C3o)alkynyl, aryl(G-C3o)alkyl, substituted (G-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl or substituted aryl(Ci-C3o)alkyl;
  • B 1 nor B 2 contains one or more of the following amino acid sequences: Arg-(Lys)2-(Arg)2-Gln-(Arg)3, Tyr-Ala-Arg-Lys-Ala-(Arg)2-Gln-Ala- (Arg) 2/ Tyr-Ala-Arg-(Ala)2-(Arg) 2 -(Ala)2-(Arg)2, Tyr-Ala-(Arg) 9 , Tyr-(Ala) 3 -(Arg) 7 , Tyr-Ala-Arg-Ala-Pro-(Arg)2-Ala-(Arg)3 or Tyr-Ala-Arg-Ala-Pro-(Arg)2-Pro-(Arg)2;
  • the invention is directed to the use of compounds of Formula (III) to treat insulin resistance in a mammalian subject, with or without weight loss, wherein B 1 is Arg-Lys-Gln-Lys-(Arg)5, Arg-(Lys)2-Arg-Gln-(Arg)4, Arg-(Lys) 2 -(Arg)3-
  • B 2 is J?-Ala, ⁇ AIa-GIy, ;?-Ala-Tyr,/?-Ala-Tyr-Gly, ( ⁇ -AIa) 2 , (/-AIa) 2 -GIy, (/?-Ala)2-Tyr, (/-Ala) 2 -Tyr-Gly, Doc, Doc-Gly, Doc-Tyr, Doc-Tyr-Gly, (Do ⁇ , (Doc) 2 - GIy, (Doc)2-Tyr, Do ⁇ -Tyr-Gly, or deleted;
  • B 3 is Arg-Lys-Gln-Lys-(Arg)s, Arg-Lys-(Arg)3-Gln-(Arg)3, Arg-(Lys)2-Arg-Gln- (Arg) 4 , Arg-(Lys)2-Gln-(Arg) 5 , Arg-(Lys)2-(Arg)2-Gln-(Arg) 3 , Arg-(Lys)2-(Arg) 3 -Gln- (Arg) 2 , Arg-(Lys)2-(Arg)4-Gln-Arg, Arg-(Lys)2-(Arg) 5 -Gln, Arg-Gln-(Lys)2-(Arg)s, Arg- Gln-(Arg) 7 , Arg-Gln-(Arg) 8 , (Arg)2-Lys-(Arg)2-Gln-(Arg)3, (Arg)2-Gln-(Arg) 6 , (Arg) 2 -
  • a 1 is A6c, Cha, hCha, Chg, D-Chg, hChg, Gaba, hLeu, Met, jG-hMet, D-2-Nal, Nip, NIe, Oic, Phe, D-Phe, hPhe, hPro, or deleted;
  • a 2 is Cys
  • a 3 is D- Abu, Aib, Ala, fi-Ala, D-AIa, D-Cha, Gaba, GIu, GIy, D-IIe, D-Leu, D- Met, D-NIe, D-Phe, D-TIe, D-Trp, D-Tyr, D-VaI, or deleted;
  • a 4 is His
  • a 5 is D-BaI, D-I-NaI, D-2-Nal, D-Phe, D-(X 1 / X 2 ,X 3 ,X 4 ,X 5 )Phe, D-Trp, or D- (Et)Tyr;
  • a 6 is Arg or hArg
  • a 7 is BaI, Bip, 1-Nal, 2-Nal, Trp, or D-Trp;
  • a 8 is A5c, A6c, Aha, Ahx, Ala, /J-AIa, Apn, Gaba, GIy 7 or deleted;
  • a 9 is Cys, D-Cys, hCys, D-hCys, Lys, Pen, or D-Pen;
  • a 10 is Pro, Thr or deleted;
  • a 11 is Pro or deleted
  • a 12 is arg, Lys, or deleted
  • a 13 is Asp or deleted; each of R 2 and R 3 is, independently, H or acyl; or pharmaceutically acceptable salts thereof.
  • Preferred ligands of the immeduiately foregoing group of compounds according to Formula (III), useful to treat insulin resistance in a mammalian subject, with or without weight loss are compounds of the formula:
  • the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor compound according to Formula (IV), and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof, with a compound having the following formula (formula (IV)):
  • a 1 is the D-isomer of X-Phe or 2-Nal where X is halogen
  • a 2 is BaI, 1-Nal, 2-Nal, or Trp;
  • a 3 is Aib, Ala, /?-Ala or GIy, or pharmaceutically acceptable salts thereof.
  • Preferred compounds of the immediately foregoing formula discovered to treat insulin resistance in a mammalian subject, with or without weight loss, include the following:
  • the invention additionally provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor compound modified with a hydantoin moiety according to Formula (V), (VI) or (VII), and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof.
  • the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor ligand according to the following formula (Formula (V)), pharmaceutically- acceptable salts, hydrates, solvates and/or prodrugs thereof (see International Patent
  • X is selected from the group consisting of -CH2-S-S-CH2-, -C(CHa) 2 -S-S-CH 2 -, -CH 2 -S-S-C(CHa) 2 -, -C(CHs) 2 -S-S-C(CHs) 2 -, -(CH 2 J 2 -S-S-CH 2 -, -CH 2 -S-S-(CH 2 J 2 -, -(CH 2 J 2 -S-S-(CH 2 )Z-, -C(CH 3 )Z-S-S-(CHz) 2 -, -(CHa) 2 -S-S-C(CHs) 2 -, -(CH 2 ).-C(O)-NR 8 - (CHz)r- and -(CH 2 ),- NR 8 -C(O)-(CH 2 ), -;
  • R 1 and R 2 each is, independently, H, (Ci-Go)alkyl or substituted (d-Cio)alkyl;
  • R 3 is -OH or -NHz
  • R 4 and R 5 each is, independently, H, (G-Cio)alkyl or substituted (Ci-Cio)alkyl;
  • a 1 is His, 2-Pal, 3-Pal, 4-Pal, (X ⁇ X 2 ,X*,X ⁇ X 5 )Phe, Taz, 2-Thi, 3-Thi or is deleted;
  • a 2 is D-BaI, D-I-NaI, D-2-Nal, D-Phe or D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe;
  • a 3 is Arg, hArg, Dab, Dap, Lys or Orn;
  • a 4 is BaI, 1-Nal, 2-Nal, (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe or Trp;
  • R 6 and R 7 each is, independently for each occurrence thereof, H, (Ci-Cio)alkyl, (Ci-Cio)heteroalkyl, aryl(Ci-Cs)alkyl, substituted (Ci-Cio)alkyl, substituted (Ci- Cio)heteroalkyl or substituted aryl(Ci-Cs)alkyl provided that R 6 and R 7 may be joined together to form a ring;
  • R 8 is H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; r is, independently for each occurrence thereof, 1, 2, 3, 4 or 5; and t is, independently for each occurrence thereof, 1 or 2.
  • a compound according the foregoing fourmula found useful to treat insulin resistance in a mammalian subject, with or without weight loss include compounds wherein X 1 is selected from the group consisting of:
  • Representative embodiments of the foregoing class of compounds useful to treat insulin resistance in a mammalian subject, with or without weight loss, are as follows: c[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:
  • the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor compound according to Formula (VI), pharmaceutically-acceptable salts, hydrates, solvates and/or prodrugs thereof (see International Patent Application Number PCT/US08/06675 which is incorporated herein by reference in its entirety):
  • a 1 is Asp, Cys, D-Cys, Dab, Dap, GIu, Lys, Orn, Pen or D-Pen;
  • a 2 is an L- or D-amino acid;
  • a 3 is His, 2-Pal, 3-Pal, 4-Pal, (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, Taz, 2-Thi or 3-Thi;
  • a 4 is D-BaI, D-I-NaI, D-2-Nal, D-Phe or D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe;
  • a 5 is Arg, hArg, Dab, Dap, Lys or Orn;
  • a 6 is BaI, 1-Nal, 2-Nal, (X ⁇ X 2 ,X 3 ,X 4 ,X 5 )Phe or Trp, ;
  • a 7 is Asp, Cys, D-Cys, Dab, Dap, GIu, Lys, Orn, Pen or D-Pen;
  • R 1 is H, (Ci-Go)alkyl or substituted (Ci-Go)alkyl;
  • R 2 and R 3 each is, independently, H, (G-Cio)alkyl, (Ci-Cio)heteroalkyl, aryl(G- Csjalkyl, substituted (Ci-Go)alkyl, substituted (G-Cio)heteroalkyl or substituted aryl(G-Cs)alkyl or R 2 and R 3 may be fused together form a cyclic moiety;
  • R 5 and R 6 each is, independently, H, (G-Go)alkyl, (G-Go)heteroalkyl, aryl(G- Cs)alkyl, substituted (G-Go)alkyl, substituted (G-Go)heteroalkyl or substituted aryl(G-C5)alkyl or R 5 and R 6 may be fused together form a cyclic moiety;
  • R 7 and R 8 each is, independently, H, (G-Go)alkyl, (G-Go)heteroalkyl, aryl(G- G)alkyl, substituted (G-Go)alkyl, substituted (G-Go)heteroalkyl or substituted aryl(G-C5)alkyl; or R 7 and R 8 may be fused together form a cyclic moiety;
  • R 9 is H, (G-Go)alkyl or substituted (G-Go)alkyl; and n is, independently for each occurrence thereof, 1, 2, 3, 4, 5, 6 or 7; or a pharmaceutically acceptable salt thereof.
  • a preferred class of compounds according to Formula (VI) useful to treat insulin resistance in a mammalian subject, with or without weight loss, are those compounds wherein:
  • a 1 is Cys
  • a 2 is D-AIa, Asn, Asp, GIn, GIu or D-Phe;
  • a 3 is His
  • a 4 is D-2-Nal or D-Phe; A 5 is Arg; A 6 is Trp; and A 7 is Cys or Pen; each of R 1 , R 2 , R 3 , and R 9 is, independently, H; R 4 is C(O)NH 2 ; each of R 5 and R 6 is, independently, H, (Ci-Cio)alkyl, (Ci-Cio)heteroalkyl, substituted (Ci-Cio)alkyl or substituted (Ci-Cio)heteroalkyl or R 5 and R 6 may be fused together form a cyclic moiety; and each of R 7 and R 8 is, independently, H, (Ci-Cio)alkyl, (Ci-Cio)heteroalkyl, substituted (Ci-Cio)alkyl or substituted (Ci-Cio)heteroalkyl; or pharmaceutically acceptable salts thereof.
  • Preferred compounds of the immediately foregoing formula (Formula (VI)) useful to treat insulin resistance in a mammalian subject, with or without weight loss include:
  • Hydantoin(C(O)-(Nle-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO:279) Hydantoin(C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279) Hydantoin(C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279) Hydantoin(C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279) Hydantoin(C(O)-(Gly-G
  • Hydantoin(C(O)-(Nle-Ala))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2 SEQ ID NO:289); or pharmaceutically acceptable salts thereof.
  • the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor ligand belonging to a class of cyclic peptide analogs that are ligands for the melanocortin receptors having a structure according to Formula (VII) as depicted below (see International Patent Application Number PCT/US08/06675 which is incorporated herein by reference in its entirety):
  • X is selected from the group consisting of -CH2-S-S-CH2-, -C(CFb) 2 -S-S-CH 2 -, -CH 2 -S-S-C(CHs) 2 -, -C(CHa) 2 -S-S-C(CHa) 2 -, -(CH 2 J 2 -S-S-CH 2 -, -CH 2 -S-S-(CH 2 J 2 , -(CH 2 )2-S-S-(CH2)2-, -C(CH 3 )Z-S-S-(CH 2 J 2 -, -(CHa) 2 -S-S-C(CHs) 2 -, -(CH 2 )t-C(O)-NR 8 - (CH 2 ),- and -(CH 2 )r NR 8 -C(O)-(CH 2 )t -; each of R 1 and R 5 is, independently, H, (Ci-Cio)alkyl
  • a 1 is an L- or D-amino acid or deleted
  • a 2 is His, 2-Pal, 3-Pal, 4-Pal, (X' ⁇ X ⁇ X ⁇ X ⁇ Phe, Taz, 2-Thi or 3-Thi;
  • a 3 is D-BaI, D-I-NaI, D-2-Nal, D-Phe or D-(X ⁇ X 2 ,X 3 ,X 4 ,X 5 )Phe;
  • a 4 is Arg, hArg, Dab, Dap, Lys or Orn,;
  • a 5 is BaI, 1-Nal, 2-Nal, (X' ⁇ X ⁇ X ⁇ Phe or Trp, ; r is, independently for each occurrence thereof, 1, 2, 3, 4 or 5; and t is, independently for each occurrence thereof, 1 or 2; or pharmaceutically acceptable salts thereof.
  • a 1 is Ala, D-AIa, Asn, Asp, GIn, GIu or GIy; or pharmaceutically acceptable salts thereof.
  • Preferred compounds according to Formula (VII) useful in the treatment of insulin resistance in a mammalian subject include the following compounds: c[Hydantoin(C(O)-(Nle-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:
  • the present invention is directed to a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor ligand according to Formula (VIII) (see International Patent Application Number
  • a 1 is Ace, HN-(CH 2 )m-C(O), an L- or D-amino acid;
  • a 2 is Asp, Cys, D-Cys, hCys, D-hCys, GIu, Pen, or D-Pen;
  • a 3 is Aib, Ala, ⁇ -P ⁇ a, Gaba, GIy or a D-amino acid
  • a 4 is His, 2-Pal, 3-Pal, 4-Pal, (X' ⁇ X ⁇ X ⁇ Phe, Taz, 2-Thi, or 3-Thi;
  • a 5 is D-BaI, D-I-NaI, D-2-Nal, D-Phe, L-Phe, D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe, D-Trp or D-(Et)Tyr;
  • a 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH 2 )n-N(R 4 R 5 ))-C(O);
  • a 7 is BaI, D-BaI, Bip, D-Bip, 1-Nal, D-I-NaI, 2-Nal, D-2-Nal, or D-Trp;
  • a 8 is Ace, Aha, Ahx, Ala, D-AIa, ⁇ -Ala, Apn, Gaba, GIy, HN-(CH 2 )S-C(O), or deleted;
  • a 9 is Cys, D-Cys, hCys, D-hCys, Dab, Dap, Lys, Orn, Pen, or D-Pen;
  • a 10 is Ace, HN-(CH 2 )t-C(O), L- or D-amino acid, or deleted;
  • R 1 is OH, or NH 2 ; each of R 2 and R 3 is, independently for each occurrence selected from the group consisting of H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (G-C3o)acyl, (C 2 -C3o)alkenyl, (C 2 -C3o)alkynyl, aryl(G-C3o)alkyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (Ci-C3o)acyl, substituted (C 2 -C3o)alkenyl, substituted (C 2 -C3o)alkynyl, substituted aryl(Ci-C3o)alkyl, and substituted aryl(Ci-
  • each of R 4 and R 5 is, independently for each occurrence, H, (Ci-G «))alkyl, (Ci-
  • (Ci-C4o)acyl substituted (Q-C4o)alkenyl, substituted (C 2 -C4o)alkynyl, substituted aryl(Ci-C4o)alkyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl, or -C(NH)-NH 2 ;
  • m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7;
  • n is, independently for each occurrence, 1, 2, 3, 4 or 5;
  • s is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7;
  • t is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7;
  • X 1 , X 2 , X 3 , X 4 , and X 5 each is, independently for each occurrence, H, F, Cl, Br, I,
  • R 4 is (Ci-C4o)acyl, aryl(Ci-C4o)acyl, substituted (Ci-C4o)acyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl, or -C(NH)-NH 2
  • R 5 is H or (Ci-Gio)alkyl, (Ci-C4o)heteroalkyl, (C2-C»o)alkenyl, (C2-C4o)alkynyl, aryl(G- C4o)alkyl, substituted (Ci-Cto)alkyl, substituted (Ci-C4o)heteroalkyl, substituted (C2- C4o)alkenyl, substituted (C2-C4o)alkynyl, or substituted aryl(Ci-G «))alkyl;
  • R 2 is (Ci-Owjacyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)acyl, or substituted aryl(Ci-C3o)acyl
  • R 3 is H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (C2- Csojalkenyl, (C2-C3o)alkynyl, aryl(Ci-C3o)alkyl, substituted (Ci-C3o)alkyl, substituted
  • a preferred group of compounds of the immediate foregoing formula useful to treat insulin resistance in a mammalian subject, with or without weight loss, is wherein
  • a 0 is 1-Nal, 2-Nal, His, Pff, Phe, Trp, or Tyr;
  • a 1 is Arg
  • a 2 is Cys
  • a 3 is D-AIa; A 4 is His;
  • a 6 is Arg
  • a 8 is deleted; A 9 is Cys; and
  • a 10 is deleted; or pharmaceutically acceptable salts thereof.
  • Preferred compounds of the immediately foregoing group of compounds is which are useful to treat insulin resistance in a mammalian subject, with or without weight loss, of the formula: Ac-Tyr-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:292) Ac-2-NaI-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:292) Ac-l-Nal-Arg-c(Cys-D-Ala-His-DPhe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-Phe-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:292) Ac-Trp-Arg-c(Cys-D-A
  • the compound or compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) as defined hereinabove which are useful to treat insulin resistance in a mammalian subject, with or without weight loss, or a pharmaceutically acceptable salt thereof, are provided to said subject in need in a composition with a pharmaceutically acceptable carrier or diluent.
  • the invention provides a method of treating insulin resistance in a subject in need thereof, comprising peripheral administration of an effective amount of a melanocorrin receptor 4 agonist to treat the insulin resistance in the subject in need thereof.
  • the melanocorrin receptor 4 agonist useful to treat insulin resistance with or without an accompanying reduction in body weight in the subject in need thereof is selected from the group consisting of:
  • ID NO:156 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;

Abstract

The present invention relates to peptide ligands of the melanocortin receptors, in particular the melancortin-4 receptor, and as such, are useful in the treatment of disorders responsive to the activation of this receptor, such as insulin resistance.

Description

USE OF MELANOCORTINS TO TREAT INSULIN SENSITIVITY BACKGROUND OF THE INVENTION
Melanocortins are a family of regulatory peptides which are formed by post- translational processing of pro-hormone pro-opiomelanocortin (POMC; 131 amino acids in length). POMC is processed into three classes of hormones; the melanocortins, adrenocorticotropin hormone, and various endorphins (e.g. lipotropin) (Cone et al, Recent Prog. Horm. Res., 51:287-317, (1996); Cone et al, Ann. N.Y. Acad. Sci., 31:342-363, (1993)).
Five melanocortin receptors (MC-R) have been characterized to date. These include melanocyte-specific receptor (MCl-R), corticoadrenal-specific ACTH receptor (MC2-R), melacortin-3 (MC3-R), melanocortin-4 (MC4-R) and melanocortin-
5 receptor (MC5-R). All of the melanocortin receptors respond to the peptide hormone class of melanocyte stimulating hormones (MSH) (Cone et al, Ann. N.Y.
Acad. Sci., 680:342-363 (1993); Cone et al., Recent Prog. Horm. Res., 51:287-318 (1996)).
There has been great interest in melanocortin (MC-R) receptors as targets for the design of novel therapeutics to treat disorders of body weight such as obesity and cachexia. One of the receptors, MC4-R, is a 332 amino acid transmembrane protein expressed in brain as well as placental and gut tissues (Cone et al., Ann. N.Y. Acad. Sci., 680:342-363 (1993); Cone et al., Recent Prog. Horm. Res., 51:287-318 (1996)). Recent pharmacological confirmation has established that central MC4-R receptors are the prime mediators of the anorexic and orexigenic effects reported for melanocortin agonists and antagonists, respectively (Giraudo et al., Brain Res., 809:302-306 (1998); Farooqi et al., NE J Med., 348:1085-1095 (2003); MacNeil et al, Eu. J. Pharm., 44:141-157 (2002); MacNeil et al., Eu. J. Pharm., 450:93-109 (2002); Kask et al., NeuroReport, 10:707-711 (1999); Chen et al.,. Transgenic Res., 9:145-54, (2000); Marsh et al, Nat Genet., 21:119-22, (1999); Balthasar et al, Cell, 123:493-505 (2005)).
Complications of body weight disorders commonly include an inability to produce and utilize insulin, often resulting in faulty glucose regulation. The consequence of failure to properly control glucose metabolism affects many aspects of overall health including energy metabolism, neuropathy and heart disease. Current progress with receptor-selective melanocortin receptor ligands evidences the therapeutic potential of melanocortin receptor activation, particularly MC4-R, in the treatment of glucose regulation, including insulin metabolism.
SUMMARY OF THE INVENTION
The present invention is directed to the use of peptides which are ligands of one or more of the melanocortin receptors (MC-R), or the pharmaceutically- acceptable salts thereof, to treat mammals suffering from insulin resistance. In one embodiment, the ligands are agonists to the melanocortin 4 receptor. In a preferred embodiment, the melanocortin receptor ligands are according to the formulae described herein or are selected from particular peptides described herein.
The insulin resistant subject mammals may be obese or overweight and may lose weight as a result of the administration of the peptides of the invention. The insulin resistant subject mammals may also be normal weight or lean. The insulin resistant condition of the subject mammals may be treated independent of weight loss. In addition, the subject mammals may be human subjects of any age, such as an infant, a child, an adult or an elderly adult.
In the first embodiment, the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor 4 ligand according to Formula (I) and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof (see International Patent Application Publication Number WO 2007/008704, incorporated herein by reference in its entirety): (R2R3)-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-R1
(I) wherein:
A1 is Ace, HN-(CH2)m-C(O), L- or D-amino acid, or deleted; A2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp, or GIu; A3 is GIy, Ala, /?-Ala, Gaba, Aib, D-amino acid, or deleted;
A4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, or (X\X2,X*,X\Xψhe;
A5 is D-Phe, D-I-NaI, D-2-Nal, D-Trp, D-BaI, D-(X1,X2,X3,X4,X5)Phe, L-Phe or D-(Et)Tyr;
A6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2)n-N(R4R5))-C(O);
A7 is Trp, 1-Nal, 2-Nal, BaI, Bip, D-Trp, D-I-NaI, D-2-Nal, D-BaI or D-Bip;
A8 is GIy, D-AIa, Ace, Ala, β-Ala, Gaba, Apn, Ahx, Aha, HN-(CH2)S-C(O), or deleted;
A9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn, or Lys;
A10 is Ace, HN-(CH2)t-C(O), L- or D-amino acid, or deleted;
R1 is OH or NH2; each of R2 and R3 is, independently for each occurrence, selected from the group consisting of H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (Ci-C3o)acyl, (C2-C3o)alkenyl, (0-C3o)alkynyl, aryl(Ci-C3o)alkyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (Ci-C3o)acyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl, substituted aryl(Ci-C3o)alkyl, and substituted aryl(Ci-
each of R4 and R5 is, independently for each occurrence, H, (Ci-Gιo)alkyl, (G-
Oojheteroalkyl, (Ci-C4o)acyl, (C2-C4o)alkenyl, (C2-C4o)alkynyl, aryl(Ci-C4o)alkyl, aryl(Ci-C4o)acyl, substituted (Ci-C4o)alkyl, substituted (Ci-C4o)heteroalkyl, substituted (Ci-C4o)acyl, substituted (C2-C4o)alkenyl, substituted (O-Gwjalkynyl, substituted aryl(Ci-C4o)alkyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl, or -C(NH)-NH2; m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; n is, independently for each occurrence, 1, 2, 3, 4 or 5; s is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7;
X1, X2, X3, X4, and X5 each is, independently for each occurrence, H, F, Cl, Br, I, (Ci-io)alkyl, substituted (Ci-io)alkyl, (C2-io)alkenyl, substituted (C2-io)alkenyl,
(C2-io)alkynyl, substituted (C2-io)alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN; provided that
(I). when R4 is (Ci-C4o)acyl, aryl(Ci-G»o)acyl, substituted (Ci-C4o)acyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl, or -C(NH)-NH2, then R5 is H or (Ci-C4o)alkyl, (Ci-C4o)heteroalkyl, (Cz-C4o)alkenyl, (C2-C«>)alkynyl, aryl(Ci- C4o)alkyl, substituted (Ci-C4o)alkyl, substituted (Ci- C4o)heteroalkyl, substituted (C2-C4o)alkenyl, substituted (C2-C4o)alkynyl, or substituted aryl(G-C4o)alkyl;
(II). when R2 is (Ci-C3o)acyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)acyl, or substituted aryl(G-C3o)acyl, then R3 is H, (Ci-Qo)alkyl, (Ci-C3o)heteroalkyl, (C2-C3o)alkenyl, (Cz-Csojalkynyl, aryl(Ci-C3o)alkyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (C2-C3o)alkenyl, substituted (C2-
C3o)alkynyl, or substituted aryl(Ci-C3o)alkyl;
(III). either A3 or A8 or both must be present in said compound;
(IV). when A2 is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen, then A9 is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen;
(V). when A2 is Asp or GIu, then A9 is Dab, Dap, Orn, or Lys;
(VI). when A8 is Ala or GIy, then A1 is not NIe; and
(VII). when A1 is deleted, then R2 and R3 cannot both be H; or pharmaceutically acceptable salts thereof. In one aspect of the first embodiment, the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a subgroup of melanocortin receptor ligands of the immediate foregoing Formula I, wherein':
A1 is A6c, Arg, D-Arg, Cha, D-Cha, hCha, Chg, D-Chg, Gaba, He, Leu, hLeu, Met, jS-hMet, 2-Nal, D-2-Nal, Nip, NIe, Oic, Phe, D-Phe, hPhe, hPro, VaI, or deleted;
A2 is Asp, Cys, D-Cys, hCys, D-hCys, GIu, Pen, or D-Pen;
A3 is D- Abu, Aib, Ala, /-Ala, D-AIa, D-Cha, Gaba, D-GIu, GIy, D-IIe, D-Leu,
D-TIe7 D-VaI, or deleted; A4 is His or 3-Pal;
A5 is D-BaI, D-I-NaI, D-2-Nal, D-Phe, D-Trp, or D-(Et)Tyr;
A6 is Arg, or hArg;
A7 is BaI, Bip, 1-Nal, 2-Nal, Trp, D-Trp;
A8 is A6c, D-AIa, Aha, Ahx, Ala, /-Ala, Apn, Gaba, GIy or deleted; A9 is Cys, D-Cys, hCys, D-hCys, Lys, Pen, or D-Pen;
A10 is Thr, or deleted; wherein at least one of A3 or A8 is deleted, but not both, or pharmaceutically acceptable salts thereof.
More preferred compounds of the immediately foregoing group of ligands according to Formula (I) useful to treat insulin resistance in a mammalian subject, with or without weight loss, are compounds of the formula:
Ac-Nle-cCAsp-His-D-Phe-Arg-Trp-^- AIa-LyS)-NH2; SEQ ID NO:1 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH2; SEQ ID NO:1 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp- Ahx-Cys)-NH2; SEQ ID NO:2 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2; SEQ ID NO:3 D-Phe-c(Cys-His-D-Phe-Arg-Trp-/-Ala-D-Cys)-Thr-NH2; SEQ ID NO:3 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2; SEQ ID NO:3 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:2 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2; SEQ ID NO:4 Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:5 Ac-D-Z-Nal-cCAsp-His-D-Phe-Arg-Trp-Gaba-LysJ-NH∑; SEQ ID NO:6 Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 Ac-Nle-c(Cys-^-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8 Ac-Nle-c(D-Cys-D- Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8 Ac-Nle-cφ-Cys-^-Ala-His-D-Phe-Arg-Trp-Cys^NH∑; SEQ ID NO:8 Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8 Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8 Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9 Ac-Nle-c(Cys-j?-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9 Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9 Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9 Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9 Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10 Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10 Ac-NIe-C(D-CyS-J?- Ala-His-D-Phe- Arg-Trp-D-Cys)-NH2; SEQ ID NO: 10 Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10 Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10 Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH>; SEQ ID NO: 11 Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11 Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-hCha-c( Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11 Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11 Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 n-butanoyl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:12 Ac-hPhe-c( Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11
Ac-/? -hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11 Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13 Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp- Ala-Lys)-NH2; SEQ ID NO:13 Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13 Ac-hLeu-cCAsp-His-D-Phe-Arg-D-Trp- AIa-LyS)-NH2; SEQ ID NO:13 Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13 Ac-Nle-cCAsp-His-D-Phe-Arg-D-Trp-D-Ala-LysJ-NH^ SEQ ID NO:14 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-^- Ala-Lys)-NH2; SEQ ID NO: 14 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH2; SEQ ID NO:14 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH2; SEQ ID NO:14 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH2; SEQ ID NO:14 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH2; SEQ ID NO: 15 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH2; SEQ ID NO:15 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp- Ahx-Cys)-NH2; SEQ ID NO: 15 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp->Ala-Cys)-NH2; SEQ ID NO:15 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH2; SEQ ID NO:15 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2; SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-l-Nal-Cys)-NH2; SEQ ID NO:16 n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO:17 n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:17 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO:18 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-l-Nal-Cys)-NH2; SEQ ID NO:18 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH2; SEQ ID NO:18 Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:61 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D- Ala-Lys)-NH2; SEQ ID NO: 19 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2; SEQ ID NO:20 Ac-Nle-cCPen-D-Ala-His-D-Phe-Arg-Trp-CysJ-NH∑; SEQ ID NO:21 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22 Ac-Nle-cCPen-D-Ala-His-D-Phe-Arg-Trp-PenJ-NH∑; SEQ ID NO:22
D-Phe-c(Cys-His-D-Phe-hArg-Trp-/?-Ala-D-Cys)-Thr-NH2; SEQ ID NO:23 D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-/?-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24 D-Phe-c(Cys-His-D-Phe-Arg-BiP:/?-Ala-D-Cys)-Thr-NH2; SEQ ID NO:25 D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24 D-Phe-c(Cys-His-D-Phe-hArg-Bip-/?-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-/?-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26 Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:27 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2; SEQ ID NO:28 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2; SEQ ID NO:28 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; SEQ ID NO:29 Ac-Nle-c(Cys-D- Abu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH_; SEQ ID NO:30 Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:31 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32 Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32 Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34 Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34 Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:35 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:36 Ac-Nle-cCCys-His-Phe-Arg-D-Trp-Gaba-Cys^NH^ SEQ ID NO:37 Ac-Nle-cCAsp-His-D^-Nal-Arg-Trp-Ala-LysJ-NPk; SEQ ID NO:38 Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-/?- Ala-Lys)-NH2; SEQ ID NO:38 Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:39 Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO:39 Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40 Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-^-Ala-Lys)-OH; SEQ ID NO:41 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH; SEQ ID NO:42 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH; SEQ ID NO:43 D-Phe-c(Cys-His-D-Phe-Arg-Trp-^-Ala-D-Cys)-Thr-OH; SEQ ID NO:43 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH; SEQ ID NO:43 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH; SEQ ID NO:42 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH; SEQ ID NO:41 Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-Nle-cCAsp-His-D-Phe-Arg-Trp-Gaba-LysJ-OH; SEQ ID NO:44 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:29 Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;SEQ ID NO:44 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH; SEQ ID NO:45 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH; SEQ ID NO:45 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-/?-Ala-Cys)-OH; SEQ ID NO:45 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH; SEQ ID NO:45 Ac-Nle-c(Cys-D- Ala-His-D-2-Nal-Arg-Trp-Cys)-OH; SEQ ID NO:46 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH; SEQ ID NO:46 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-l -Nal-Cys)-OH; SEQ ID NO:46 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH; SEQ ID NO:46 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:47 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; SEQ ID NO:29 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH; SEQ ID NO:48
Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:50 Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:50 Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:51 Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:52 Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:52 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:51 Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp- AIa-LyS)-NH2; SEQ ID NO:53 Ac-Arg-c(Asp-His-D-Phe-Arg-Trp- AIa-LyS)-NH2; SEQ ID NO:53 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-/?-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24 Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:27 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32 Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34 Ac-Nle-ctAsp-His-D-Phe-Arg-Trp-^-Ala-LysJ-NH-; SEQ ID NO:1 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp- Ahx-Cys)-NH2; SEQ ID NO:2
D-Phe-cCCys-His-D-Phe-Arg-Trp-^-Ala-D-CysJ-Thr-NH^ SEQ ID NO:3 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2; SEQ ID NO:3 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:2 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2; SEQ ID NO:4 Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6 Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11 Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-/?-Ala-Cys)-NH2; SEQ ID NO: 15 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:21 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22 D-Phe-c(Cys-His-D-Phe-hArg-Trp:/?-Ala-D-Cys)-Thr-NH2; SEQ ID NO:23 D-Phe-c(Cys-His-D-Phe-Arg-Bip-^-Ala-D-Cys)-Thr-NH2; SEQ ID NO:25
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-^Ala-D-Cys)-Thr-NH2; SEQ ID NO:24 D-Phe-c(Cys-His-D-Phe-hArg-Bip-^-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26 D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-^-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26 Ac-Nle-cCAsp-D-Ala-His-D-Phe-Arg-Trp-LysJ-NH∑; SEQ ID NO:28 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2; SEQ ID NO:28 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; SEQ ID NO:29 Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Cys-D- Val-His-D-Phe- AFg-TFp-CyS)-NH2; SEQ ID NO:30 Ac-Nle-c(Cys-D-Ile-His-D-Phe- Arg-Trp-CysJ-Nrfc; SEQ ID NO:30 Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-cCCys-D-Tle-His-D-Phe-Arg-Trp-CysJ-N^; SEQ ID NO:30 Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:31 Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32 Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34
Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:35 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:36 Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH2; SEQ ID NO:37 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2; SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D-2-NaI-Arg-Bal-Cys)-NH2; SEQ ID NO:20 Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO:38 Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β- AIa-LyS)-NH2; SEQ ID NO:38 Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:39 Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp- Ahx-Cys)-NH2; SEQ ID NO:39
Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40 Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40 or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49 or pharmaceutically acceptable salts thereof. In the second embodiment, the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor ligand according to Formula (II) and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof (see International Patent Application Publication Number WO 2007/008704 incorporated herein by reference in its entirety):
(R2R3)-A'-c(A2-A3-A4-A5-A6-A7-A8-A9)-NH2
(H) wherein:
A1 is NIe or deleted;
A2 is Cys or Asp;
A3 is GIu or D-AIa; A4 is His;
A5 is D-Phe;
A6 is Arg;
A7 is Trp, 2-Nal or BaI;
A8 is GIy, Ala, D-AIa, β-Ala, Gaba or Apn; A9 is Cys or Lys; each of R2 and R3 is independently selected from the group consisting of H or
Figure imgf000013_0001
provided that
(I). when R2 is (Ci-C6)acyl, then R3 is H; and (II). when A2 is Cys, then A9 is Cys, or a pharmaceutically acceptable salt thereof.
More preferred of the immediately foregoing group of compounds which are useful to treat insulin resistance in a mammalian subject, with or without weight loss, are compounds of the formula: Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH2; SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH2; SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β- AIa-CyS)-NH2; SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:54 Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:55 Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2; SEQ ID NO:55 Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:56 Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal- AIa-CyS)-NH2; SEQ ID NO:56 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:57 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β- Ala-Cys)-NH2; SEQ ID NO:57
Ac-Nle-c(Cys-D- Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:57 or Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal- AIa-LyS)-NH2; SEQ ID NO:58 or a pharmaceutically acceptable salt thereof.
In the third embodiment, the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor compound according to Formula (III), and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof (see International Application Publication Number WO 2007/008684, incorporated herein by reference in its entirety): (R2R3)-B'-A1-c(A2-A3-A4-A5-A6-A7-A8-A9)-A10-A11-A12-A13-B2-B3-R1
(III) wherein:
B1 is a peptide moiety which contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ,or 15 amino acids, wherein at least 5 amino acids are independently selected from the group consisting of L-Arg, D-Arg, L-hArg and D-hArg, or B1 is optionally deleted;
A1 is Ace, HN-(CH2)m-C(O), L- or D-amino acid or deleted; A2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or GIu;
A3 is GIy, GIu, Ala,/?-Ala, Gaba, Aib, D-amino acid or deleted; A4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi or (X1,X2,X3,X4,X5)Phe; A5 is D-Phe, D-I-NaI, D-2-Nal, D-Trp, D-BaI, D-(X',X2,X3,X4,X5)Phe, D-(Et)Tyr, D-Dip, D-Bip or D-Bpa ; A6 is Arg, hArg, Dab, Dap, Lys, Orn or HN-CH((CH2)n-N(R4R5))-C(O);
A7 is Trp, 1-NaI, 2-Nal, BaI, Bip, Dip, Bpa, D-Trp, D-I-NaI, D-2-Nal, D-BaI, D- Bip, D-Dip or D-Bpa;
A8 is GIy, D-AIa, Ace, Ala, ^-AIa, Gaba, Apn, Ahx, Aha, HN-(CH2)s-C(O) or deleted; A9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn or Lys;
A10 is Ace, HN-(CH2)I-C(O), Pro, hPro, 3-Hyp, 4-Hyp, Thr, an L- or D-amino acid or deleted;
A11 is Pro, hPro, 3-Hyp, 4-Hyp or deleted; A12 is Lys, Dab, Dap, Arg, hArg or deleted; A13 is Asp, GIu or deleted;
B2 is a peptide moiety containing 1, 2, 3, 4, or 5 amino acids or deleted, B3 is a peptide moiety which contains 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acids wherein at least 5 amino acids are independently selected from the group consisting of L-Arg, D-Arg, L-hArg and D-hArg, or is deleted;
R1 is OH or NH2; R2 and R3 each is , independently for each occurrence, selected from the group consisting of H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (Ci-C3o)acyl, (C2-C3o)alkenyl, (G- C3o)alkynyl, aryl(Ci-C3o)alkyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (Ci-C3o)acyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl, substituted aryl(G-C3o)alkyl and substituted aryl(G-C3o)acyl; R4 and R5 each is, independently for each occurrence, H, (Ci-C4o)alkyl, (G-
C4o)heteroalkyl, (Ci-C4o)acyl, (C2-C4o)alkenyl, (C2-C4o)alkynyl, aryl(Ci-C4o)alkyl, aryl(Ci-C4o)acyl, substituted (Ci-C4o)alkyl, substituted (Ci-C4o)heteroalkyl, substituted (Ci-C4o)acyl, substituted (C2-C4o)alkenyl, substituted (G-C4o)alkynyl, substituted aryl(Ci-C4o)alkyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl or C(NH)-NH2; n is, independently for each occurrence, 1, 2, 3, 4 or 5; m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; s is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7;
X1, X2, X3, X4 and X5 each is, independently for each occurrence, H, F, Cl, Br, I, (Ci-io)alkyl, substituted (G-io)alkyl, (C2-io)alkenyl, substituted (G-io)alkenyl, (G- io)alkynyl, substituted (G-io)alkynyl, aryl, substituted aryl, OH, NH2, NO2 or CN; provided that:
(I) when R4 is (Ci-C4o)acyl, aryl(G-C4o)acyl, substituted (Ci-C4o)acyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl or C(NH)-NH2, then R5 is H, (G- Go)alkyl, (G-Go)heteroalkyl, (G-Cφlkenyl, (G-Go)alkynyl, aryl(G-Go)alkyl, substituted (G-Go)aLkyl, substituted (G-Go)heteroalkyl, substituted (C2-C4o)alkenyl, substituted (G-Go)alkynyl or substituted aryl(G-Cio)alkyl;
(II) when R2 is (G-Go)acyl, aryl(G-C3o)acyl, substituted (G-C3o)acyl or substituted aryl(G-C3o)acyl, then R3 is H, (G-Qo)alkyl, (G-C3o)heteroalkyl, (G- C3o)alkenyl, (G-C3o)alkynyl, aryl(G-C3o)alkyl, substituted (G-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl or substituted aryl(Ci-C3o)alkyl;
(III) neither B1 nor B2 contains one or more of the following amino acid sequences: Arg-(Lys)2-(Arg)2-Gln-(Arg)3, Tyr-Ala-Arg-Lys-Ala-(Arg)2-Gln-Ala- (Arg)2/ Tyr-Ala-Arg-(Ala)2-(Arg)2-(Ala)2-(Arg)2, Tyr-Ala-(Arg)9, Tyr-(Ala)3-(Arg)7, Tyr-Ala-Arg-Ala-Pro-(Arg)2-Ala-(Arg)3 or Tyr-Ala-Arg-Ala-Pro-(Arg)2-Pro-(Arg)2;
(IV) either B1 or B2 or both must be present in said compound;
(V) when A2 is Cys, D-Cys, hCys, D-hCys, Pen or D-Pen, then A9 is Cys, D-Cys, hCys, D-hCys, Pen or D-Pen; and (VI) when A2 is Asp or GIu, then A9 is Dab, Dap, Orn or Lys; or pharmaceutically acceptable salts thereof.
In one aspect of the third embodiment, the invention is directed to the use of compounds of Formula (III) to treat insulin resistance in a mammalian subject, with or without weight loss, wherein B1 is Arg-Lys-Gln-Lys-(Arg)5, Arg-(Lys)2-Arg-Gln-(Arg)4, Arg-(Lys)2-(Arg)3-
Gln-(Arg)2, Arg-(Lys)2-(Arg)4-Gln-Arg, Arg-(Lys)2-(Arg)5-Gln, Arg-(Lys)2-Gln-(Arg)s, Arg-Gln-(Lys)2-(Arg)5, Arg-Gln-(Arg)?, Arg-Gln-(Arg)s, (Arg)2-Gln-(Arg)6, (Arg)2-Gln- (Arg)7, (Arg)3-Gln-(Arg)5, (Arg)3-Gln-(Arg)6, (Arg)4-Gln-(Arg)4, (Arg)4-Gln-(Arg)5, (Arg)5, (Arg)5-Gln-(Arg)3, (Arg)5-Gln-(Arg)4, (Arg)6, (Arg)6-Gln-(Arg)3, (Arg)7, (Arg)7- Gln-(Arg)2, (Arg)s, (Arg)8-Gln-Arg, (Arg)9, (Arg)9-Gln, (D-Arg)s, (D-Arg)e, (D-Arg)7, (D-Arg)8, (D-Arg)9, Gln-Arg-(Lys)2-(Arg)5, Gln-(Arg)8, Gln-(Arg)9, Tyr-Gly-Arg- (Lys)2-(Arg)2-Gln-(Arg)3, Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-Doc; or deleted;
B2 is J?-Ala, ^AIa-GIy, ;?-Ala-Tyr,/?-Ala-Tyr-Gly, (^-AIa)2, (/-AIa)2-GIy, (/?-Ala)2-Tyr, (/-Ala)2-Tyr-Gly, Doc, Doc-Gly, Doc-Tyr, Doc-Tyr-Gly, (Doφ, (Doc)2- GIy, (Doc)2-Tyr, Doφ-Tyr-Gly, or deleted;
B3 is Arg-Lys-Gln-Lys-(Arg)s, Arg-Lys-(Arg)3-Gln-(Arg)3, Arg-(Lys)2-Arg-Gln- (Arg)4, Arg-(Lys)2-Gln-(Arg)5, Arg-(Lys)2-(Arg)2-Gln-(Arg)3, Arg-(Lys)2-(Arg)3-Gln- (Arg)2, Arg-(Lys)2-(Arg)4-Gln-Arg, Arg-(Lys)2-(Arg)5-Gln, Arg-Gln-(Lys)2-(Arg)s, Arg- Gln-(Arg)7, Arg-Gln-(Arg)8, (Arg)2-Lys-(Arg)2-Gln-(Arg)3, (Arg)2-Gln-(Arg)6, (Arg)2- Gln-(Arg)7, (Arg)3-Gln-(Arg)5, (Arg)3-Gln-(Arg)6, (Arg)4-Gln-(Arg)4, (Arg)4-Gln-(Arg)5, (Arg)5, (Arg)5-Gln-(Arg)3, (Arg)5-Gln-(Arg)4, (Arg)6, (Arg)6-Gln-(Arg)3, (Arg)7, (Arg)7- GIn-(AFg)2, (Arg)β, (Arg)8-Gln-Arg, (ArgH (Arg)9-Gln, (D-Arg)s, (D-Arg)6/ (D-AFg)7, (D-AFg)8, (D-ArgH Gln-Arg-(Lys)2-(Arg)5, GIn-(AFg)8, GIn-(AFg)9, or deleted;
A1 is A6c, Cha, hCha, Chg, D-Chg, hChg, Gaba, hLeu, Met, jG-hMet, D-2-Nal, Nip, NIe, Oic, Phe, D-Phe, hPhe, hPro, or deleted; A2 is Cys
A3 is D- Abu, Aib, Ala, fi-Ala, D-AIa, D-Cha, Gaba, GIu, GIy, D-IIe, D-Leu, D- Met, D-NIe, D-Phe, D-TIe, D-Trp, D-Tyr, D-VaI, or deleted;
A4 is His;
A5 is D-BaI, D-I-NaI, D-2-Nal, D-Phe, D-(X1 /X2,X3,X4,X5)Phe, D-Trp, or D- (Et)Tyr;
A6 is Arg or hArg;
A7 is BaI, Bip, 1-Nal, 2-Nal, Trp, or D-Trp;
A8 is A5c, A6c, Aha, Ahx, Ala, /J-AIa, Apn, Gaba, GIy7 or deleted;
A9 is Cys, D-Cys, hCys, D-hCys, Lys, Pen, or D-Pen; A10 is Pro, Thr or deleted;
A11 is Pro or deleted;
A12 is arg, Lys, or deleted;
A13 is Asp or deleted; each of R2 and R3 is, independently, H or acyl; or pharmaceutically acceptable salts thereof.
Preferred ligands of the immeduiately foregoing group of compounds according to Formula (III), useful to treat insulin resistance in a mammalian subject, with or without weight loss, are compounds of the formula:
Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-NH2; (SEQ ID NO:60)
Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-Doc-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)- NH2; (SEQ ID NO:61)
Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)->Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3- NH2; (SEQ ID NO:62) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys):/?-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln- (Arg)3-NH2; (SEQ ID NO:62) Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-
NH2; (SEQ ID NO:63)
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Pro)2-Lys-Asp-Tyr-Gly-Arg-(Lys)2-(Arg)2-
Gln-(Arg)3-NH2; (SEQ ID NO:64) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Gly-Cys)-(Pro)2-Lys-Asp-Tyr-Gly-Arg-(Lys)2-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:65)
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(/?-Ala)2-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-
(AFg)3-NH2; (SEQ ID NO:66)
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Pro)2-Lys-Asp-Doc-Tyr-Gly-Arg-(Lys)2- (AFg)2-GIn-(AFg)3-NH2; (SEQ ID NO:67)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Gly-Cys)-(Pro)2-Lys-Asp-Doc-Tyr-Gly-Arg-
(LyS)2-(AFg)2-GIn-(AFg)3-NH2; (SEQ ID NO:68)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-
(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:69) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-Doc-Tyr-Gly-Arg-
(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:69)
Ac-NIe-C(ASp-HiS-D^-NaI-AFg-TrP-LyS)-(DoC)2-TyF-GIy-AFg-(LyS)2-(AFg)2-GIn-
(AFg)3-NH2; (SEQ ID NO:70)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg- (Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:71)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-(Arg)5-Gln-
(AFg)3-NH2; (SEQ ID NO:72)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Gly-(Arg)5-Gln-
(AFg)3-NH2; (SEQ ID NO:73) Ac<Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-j!?-Ala-Tyτ-Gly-(Arg)5-
GIn-(AFg)3-NH2; (SEQ ID NO:74)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-Arg-
(Lys)2-Arg-Gln-(Arg)4-NH2; (SEQ ID NO:75)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-Arg- (Lys)2-Gln-(Arg)s-NH2; (SEQ ID NO:76) Ac-C(CyS-GIu-HiS-D-Z-NaI-AFg-TrP-AIa-CyS)-(PrO)2-LyS-ASp-Z-AIa-TyF-GIy-AFg-
Lys-Gln-Lys-(Arg)5-NH2; (SEQ ID NO:77)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Tyr-Gly-Arg-
(LyS)2-(AFg)4-GIn-AFg-NH2; (SEQ ID NO:78) Ac-C(CyS-GIu-HiS-D-Z-NaI-AFg-BaI-AIa-CyS)-(PrO)2-LyS-ASp-^-AIa-TyF-AIb-AFg-
(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:79)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp-j3-Ala-(Arg)s-Gln-
(AFg)3-NH2; (SEQ ID NO:80)
Ac-C(CyS-GIu-HiS-D-Z-NaI-AFg-I-NaI-AIa-CyS)-(PrO)2-LyS-ASp-Z-AIa-(AFg)5-GIn- (AFg)3-NH2; (SEQ ID NO:80)
Ac-C(CyS-GIu-HiS-D-Z-NaI-AFg-I-NaI-AIa-CyS)-(PrO)2-LyS-ASp-Z-AIa-(AFg)6-GIn-
(AFg)3-NH2; (SEQ ID NO:81)
Ac-C(CyS-GIu-HiS-D-Z-NaI-AFg-Z-NaI-AIa-CyS)-(PrO)2-AFg-ASp-Z-AIa-(AFg)5-GIn-
(AFg)3-NH2; (SEQ ID NO:8Z) Ac-C(CyS-GIu-HiS-D-Z-NaI-AFg-Z-NaI-AIa-CyS)-(PrO)2-LyS-ASp-Z-AIa-(AFg)5-GIn-
(AFg)3-NH2; (SEQ ID NO:8Z)
Ac-C(CyS-GIu-HiS-D-Z-NaI-AFg-Z-NaI-AIa-CyS)-(PrO)2-LyS-ASp-Z-AIa-(AFg)6-GIn-
(AFg)3-NH2; (SEQ ID NO:81)
Ac-C(CyS-GIu-HiS-D-Z-NaI-AFg-BaI-AIa-CyS)-(PrO)2-AFg-ASp-Z-AIa-(AFg)6-GIn- (AFg)3-NH2; (SEQ ID NO:83)
Ac-C(CyS-GIu-HiS-D-Z-NaI-AFg-BaI-AIa-CyS)-(PrO)2-AFg-ASp-Z-AIa-(AFg)5-GIn-
(AFg)3-NH2; (SEQ ID NO:84)
Ac-C(CyS-GIu-HiS-D-Z-NaI-AFg-BaI-AIa-CyS)-(PrO)2-LyS-ASp-Z-AIa-(AFg)6-GIn-
(AFg)3-NH2; (SEQ ID NO:83) Ac-C(CyS-GIu-HiS-D-Z-NaI-AFg-TrP-AIa-CyS)-(PrO)2-LyS-ASp-Z-AIa-TyF-GIy-AFg-
(Lys)2-(Arg)3-Gln-(Arg)2-NH2; (SEQ ID NO:85)
Ac-C(CyS-GIu-HiS-D-Z-NaI-AFg-TrP-AIa-CyS)-(PrO)2-LyS-ASp-Z-AIa-TyF-GIy-AFg-
GIn-(LyS)2-(AFg)5-NHa; (SEQ ID NO:86)
Ac-C(CyS-GIu-HiS-D-Z-NaI-AFg-TrP-AIa-CyS)-(PrO)2-LyS-ASp-Z-AIa-TyF-GIy-AFg- (Lys)2-(Arg)5-Gln-NH2; (SEQ ID NO:87) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/?-AIa-Tyr-Gly-Arg-
(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:71)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-
(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:71) Ac-C(CyS-GIu-HiS-D-Z-NaI-AFg-I-NaI-AIa-CyS)-(PrO)2-LyS-ASp-^-AIa- (Arg)2-Lys-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:88)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Arg-Lys-
(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:89)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala- (Arg)2-Lys- (Arg)2-Gkv(Arg)3-NH2; (SEQ ID NO:88)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-(Arg)2-
Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:90)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Gly-(Arg)2-Lys-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:91) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Gly-Arg-Lys-
(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:92)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala- (Arg)2-Lys-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:93)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Arg-Lys- (Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:94)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)2-
Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:95)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Tyr-Gly-Arg-
Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:96) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Gly-(Arg)2-Lys-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:97)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Gly-Arg-Lys-
(Arg)3-GuΛ-(Arg)3-NH2; (SEQ ID NO:92)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-(Arg)2-Lys- (Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:98) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Arg-Lys-
(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:99)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)2-
Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 100) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-
Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:101)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys- Asp-^-Ala-Gly^Arg^-Lys-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:102)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp->Ala-Gly-Arg-Lys- (Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:103)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala- (Arg)2-Lys-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:104)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Arg-Lys-(Arg)3-
GIn-(AFg)3-NH2; (SEQ ID NO:105) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Tyr-Gly-(Arg)2-
Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:100)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-Lys-
(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:101)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Gly-(Arg)2-Lys- (Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:102)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Gly-Arg-Lys-
(Arg)3-Gln-( AFg)3-NH2; (SEQ ID NO:103)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-
(LyS)2- Arg-Gln-(Arg)4-NH2; (SEQ ID NO: 106) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Tyr-Gly-Arg-
(LyS)2-GIn-(AFg)5-NH2; (SEQ ID NO:107)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-
Lys-Gln-Lys-(Arg)5-NH2; (SEQ ID NO:108)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp->Ala-Tyr-Gly-Arg- Gln-(Lys)2-(Arg)5-NH2; (SEQ ID NO:109) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-
(Lys)2-(Arg)3-Gln-(Arg)2-NH2; (SEQ ID NO:110)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-Arg-
(Lys)2-(Arg)4-Gln-Arg-NH2; (SEQ ID NO:111) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-
(Lys)2-(Arg)5-Gln-NH2; (SEQ ID NO:112)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:113)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp-/-Ala-(Arg)5-Gln- (Arg)3-NH2; (SEQ ID NO:113)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)3-NH2; (SEQ ID NO:114)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-Tyr-Gly-(Arg)5-
GIn-(AFg)3-NH2; (SEQ ID NO: 114) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:115)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp-^-Ala-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:115)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-j?-Ala-Tyr-Gly-(Arg)5- Gln-(Arg)4-NH2; (SEQ ID NO:116)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)4-NH2; (SEQ ID NO:116)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-(Arg)5-Gln-
(AFg)3-NH2; (SEQ ID NO:117) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:117)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:118)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp-j3-Ala-(Arg)5-Gln- (AFg)4-NH2; (SEQ ID NO:118) Ac-C(CyS-GIu-HiS-D^-NaI-AFg-I-NaI-AIa-CyS)-(PrO)2-LyS- Asp-j?-Ala-(Arg)6-Gln-
(AFg)3-NH2; (SEQ ID NO:119)
Ac-C(CyS-GIu-HiS-D^-NaI-AFg-I-NaI-AIa-CyS)-(PrO)2- Arg-Asp-/?-Ala-(Arg)6-Gln-
(AFg)3-NH2; (SEQ ID NO:119) Ac-C(CyS-GIu-HiS-D-Z-NaI-AFg-I-NaI-AIa-CyS)-(PrO)2-LyS-ASp-Jj-AIa-TyF-GIy-(AFg)5-
GIn-(AFg)3-NH2; (SEQ ID NO: 120)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-Tyr-Gly-
(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:120)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-(Arg)5- Gln-(Arg)4-NH2; (SEQ ID NO:121)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-Tyr-Gly-
(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:121)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-j3-Ala-Tyr-Gly-(Arg)6-
GIn-(AFg)3-NH2; (SEQ ID NO:122) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-Tyr-Gly-
(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO:122)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-(Arg)5-Gln-
(AFg)3-NH2; (SEQ ID NO:123)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-/-Ala-(Arg)5-Gln- (Arg)3-NH2; (SEQ ID NO:123)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-(Arg)6-Gln-
(AFg)3-NH2; (SEQ ID NO:124)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-^-Ala-(Arg)6-Gln-
(AFg)3-NH2; (SEQ ID NO:124) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-(Arg)5-Gln-
(AFg)4-NH2; (SEQ ID NO:125)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-(Arg)5-Gln-
(AFg)4-NH2; (SEQ ID NO.125)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-(Arg)5- GIn-(AFg)3-NH2; (SEQ ID NO:126) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-Tyr-Gly-
(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:126)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-(Arg)6-
Gln-(Arg)3-NH2; (SEQ ID NO:127) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-j8-Ala-Tyr-Gly-
(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO:127)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-(Arg)5-
GIn-(AFg)4-NH2; (SEQ ID NO:128)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-j?-Ala-Tyr-Gly- (Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:128)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:129)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-/?-Ala-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:129) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-(Arg)5-Glii-
(Arg)4-NH2; (SEQ ID NO:130)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-/-Ala-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:130)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-(Arg)6-Gln- (Arg)3-NH2; (SEQ ID NO:131)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-(Arg)6-Gln-
(Arg)3-NH2; (SEQ ID NO:131)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Gly-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:132) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp->Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)3-NH2; (SEQ ID NO:133)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-^-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)3-NH2; (SEQ ID NO:133)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)5- GIn-(AFg)4-NH2; (SEQ ID NO:134) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)4-NH2; (SEQ ID NO:134)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)6-
Gln-(Arg)3-NH2; (SEQ ID NO:135) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-Tyr-Gly-(Arg)6-
Gln-(Arg)3-NH2; (SEQ ID NO:135)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-
(Arg)3-NH2; (SEQ ID NO:136)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys):/?-Ala-Tyr-Gly-Arg-(Lys)2-Arg-Gln- (Arg)4-NH2; (SEQ ID NO:137)
Ac-Nle-c(Cys-D- Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-
(ATg)3-NH2; (SEQ ID NO:136)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:138) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-^-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:138)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-^Ala-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:138)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:139)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys):/?-Ala-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:140)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys):/?-Ala-Tyr-Gly-(Arg)2-Lys-(Arg)2-Gln-
(Arg)3-NH2; (SEQ ID NO:141) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-/-Ala-Tyr-Gly-Arg-Lys-(Arg)3-Gln-
(AFg)3-NH2; (SEQ ID NO:142)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-^-Ala-Gly-(Arg)2-Lys-(Arg)2-Gln-
(Arg)3-NH2; (SEQ ID NO:141)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)->Ala-Gly-Arg-Lys-(Arg)3-Gln-(Arg)3- NH2; (SEQ ID NO:142) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-/-Ala- (Arg)2-Lys-(Arg)2-Gln-(Arg)3-
NH2; (SEQ ID NO:143)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-j?-Ala-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2;
(SEQ ID NO:144) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-/^Ala-Tyr-Gly-Arg-(Lys)2-Arg-Gln-
(Arg)4-NH2; (SEQ ID NO:145)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-
(Arg)3-NH2; (SEQ ID NO:146)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)->Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:148)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys):/?-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:147)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:147) Ac-Nle-c(Cys-D- Ala-His-D-Phe-Arg-Trp-Cys)-(^-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:148)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(^-Ala)2-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:149)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)s-Gln-(Arg)3- NH2; (SEQ ID NO:149)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:151)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:150) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO: 150)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:151)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:152) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO: 152)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)->Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:154) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-/-Ala-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:153)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:153)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2, (SEQ ID NO:154)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:155)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:155) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-( Arg)4-NH2; (SEQ ID
NO: 157)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO: 156)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:156)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:157)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:158) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:158)
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:159)
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:160) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)->Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:161)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:162) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)->Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:164)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-^-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:163)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys):/?-Ala-(Arg)5-Glii-(Arg)3-NH2; (SEQ ID NO:163)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:164)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(/?-Ala)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:165) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(^-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:165)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:166)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:166)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:168)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO: 167) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:167)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:168)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:170) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-/-Ala-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:169)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys):/?-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:169) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(/?-Ala)2-Tyr-Gly-(Arg)s-Gln-(Arg)4-NH2;
(SEQ ID NO: 170)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(^-Ala)2-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:171)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:171)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:173)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO: 172) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:172)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:173)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:174)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:174)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp:/?-Ala-Lys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:175) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-^-Ala-Lys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:176)
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:177)
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:178) D-Phe-c(Cys-His-D-Phe-Arg-Trp->Ala-D-Cys)-Thr-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:179)
D-Phe-c(Cys-His-D-Phe-Arg-TrP:/?-Ala-D-Cys)-Thr->Ala-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:180) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:181)
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:182)
Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:183)
Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:184)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:183) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:185)
Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:186)
Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:185)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:186)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO: 188) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(^-Ala)2-Tyr-Gly-(Arg)s-Gln-(Arg)3-
NH2; (SEQ ID NO:187)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(/?-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:188)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:189) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-(Arg)s-Gln-(Arg)3-NH2; (SEQ ID
NO:190)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:189) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:190)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO: 191)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys):/?-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:192)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:191)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:192) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:193)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-(Arg)5-Glri-(Arg)4-NH2; (SEQ ID
NO:194)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4- NH2; (SEQ ID NO:193)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:194)
Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:195) Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:196)
Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:197)
Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:198) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:199)
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:200) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)->Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:199)
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:200)
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp:/?-Ala-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3- NH2; (SEQ ID NO:201)
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp:/?-Ala-Cys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:202)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:203) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-/-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:203)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:205)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3- NH2; (SEQ ID NO:204)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(^-Ala)2-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:204)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(^-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:205) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:207)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:206)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:206) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:207)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(Doc)2-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:208) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:208)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-TrP:/?-Ala-D-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:209)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-^-Ala-D-Cys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:210)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys):/?-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:209)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys)-^-Ala-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:211) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-/-Ala-D-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:212)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-/-Ala-D-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:213)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-TrP:/?-Ala-D-Cys)-(/?-Ala)2-Gly-(Arg)5-GLn-(Arg)3- NH2; (SEQ ID NO:213)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-TrP:/?-Ala-D-Cys)-(^-Ala)2-(Arg)5-Glii-(Arg)4-NH2;
(SEQ ID NO:267)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-^-Ala-D-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:214) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-/-Ala-D-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:216)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-^-Ala-D-Cys)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:214)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys)-Doc-(Arg)5-GIn-(Arg)4-NH2; (SEQ ID NO:217) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:215)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-^-Ala-D-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:216) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:215)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:217)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-/-Ala-D-Cys)-Thr-^-Ala-Tyr-Gly-(Arg)5-Gln- (Arg)3-NH2; (SEQ ID NO:218)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr:/?-Ala-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:219)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:218) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-/-Ala-D-Cys)-Thr-(/?-Ala)2-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:219)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:221)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-^-Ala-D-Cys)-Thr-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:220)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-/-Ala-D-Cys)-Thr-(Doc)2-Tyr-Gly-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:221)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr-^-Ala-Tyr-Gly-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:222) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-^-Ala-D-Cys)-Thr:/?-Ala-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:223)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-
(AFg)4-NH2; (SEQ ID NO.222)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr-(/?-Ala)2-(Arg)5-Gln-(Arg)4- NH2; (SEQ ID NO:223) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-JJ-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)s-Gln-
(AFg)4-NH2; (SEQ ID NO:224)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-^-Ala-D-Cys)-Thr-Doc-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:225) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-/-Ala-D-Cys)-Thr-(Doc)2-Tyr-Gly-(Arg)5-Gln-
(AFg)4-NH2; (SEQ ID NO:224)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-/-Ala-D-Cys)-Thr-(Doc)2-(Arg)5-Gln-(Arg)4-
Figure imgf000035_0001
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip:/?-Ala-D-Cys)-Thr-/-Ala-Tyr-Gly-(Arg)5-Gln- (Arg)3-NH2; (SEQ ID NO:227)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip:/?-Ala-D-Cys)-Thr-:/?-Ala-Tyr-Gly-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:226)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip:/?-Ala-D-Cys)-Thr:/?-Ala-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:228) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip:/?-Ala-D-Cys)-Thr-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:227)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-/-Ala-D-Cys)-Thr-(^-Ala)2-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:228)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip:/?-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln- (Arg)3-NH2; (SEQ ID NO:229)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-^-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln-
(AFg)4-NH2; (SEQ ID NO:230)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-/-Ala-D-Cys)-Thr-Doc-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:232) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-/-Ala-D-Cys)-Thr-(Doc)2-Tyr-Gly-(Arg)5-Gln-
(AFg)3-NH2; (SEQ ID NO:231)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-^-Ala-D-Cys)-Thr-(Doc)2-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:232)
Ac-NIe-C(CyS-D-AIa-HiS-D-PHe-AFg-TrP-GIy-CyS)-^-AIa-TyF-GIy-(AFg)5-GIn-(AFg)3- NH2; (SEQ ID NO:233) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:234)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:235) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:236)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:235)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(/?-Ala)2-(Arg)s-Gln-(Arg)3-NH2; (SEQ ID NO:236)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:237)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-j?-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:238) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:237)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:238)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:239)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:240)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-Tyr-Gly-(Arg)s-Gln-(Arg)3-NH2;
(SEQ ID NO:239) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:240)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:241)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-(Arg)5-Glri-(Arg)4-NH2; (SEQ ID NO:242) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:241)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:242) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-/?-Ala-Tyr-Gly-(Arg)s-Gln-(Arg)3-NH2;
(SEQ ID NO.243)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys):/?-Ala-(Arg)5-Glii-(Arg)3-NH2; (SEQ ID
NO:244)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3- NH2; (SEQ ID NO:243)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(^-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:244)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:245) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:246)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)s-Gln-(Arg)3-
NH2; (SEQ ID NO:245)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:246)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:247)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-^-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:248) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:247)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:248)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:249) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:250)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:249) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:250)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:251)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ m NO:252)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:251)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:252) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:253)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:254)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3- NH2; (SEQ ID NO:253)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:254)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-/-Ala-Tyr-Gly-(Arg)s-Gln-(Arg)4-NH2;
(SEQ ID NO:255) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-/-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:256)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:255)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:256) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:257)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:258) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:257)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:258)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:259)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:260)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:259) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:260)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:261)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-^-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:262)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:261)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:262) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:263)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:264)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:263) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:264)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-Tyr-Gly-(Arg)s-Gln-(Arg)4-NH2; (SEQ
ID NO:265) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:266)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:265) or
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-(Arg)5-Glri-(Arg)4-NH2; (SEQ ID NO:266); or pharmaceutically acceptable salts thereof.
In a fourth embodiment, the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor compound according to Formula (IV), and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof, with a compound having the following formula (formula (IV)):
Ac-c(Cys-Glu-His-A1-Arg-A2-A3-Cys)-(Pro)2-Lys-Asp-NH2
(IV) wherein:
A1 is the D-isomer of X-Phe or 2-Nal where X is halogen;
A2 is BaI, 1-Nal, 2-Nal, or Trp; and
A3 is Aib, Ala, /?-Ala or GIy, or pharmaceutically acceptable salts thereof. Preferred compounds of the immediately foregoing formula discovered to treat insulin resistance in a mammalian subject, with or without weight loss, include the following:
Ac-c(Cys-Glu-His-D-4-Br-Phe-Arg-Trp-Gly-Cys)-(Pro)2-Lys-Asp-NH2, (SEQ ID
NO:268) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID NO:269) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID
NO:269)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID
NO:269) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys- Asp-NH2; (SEQ ID NO:2690)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal->Ala-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID
NO:270) or
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Aib-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID
NO:270) or pharmaceutically acceptable salts thereof.
The invention additionally provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor compound modified with a hydantoin moiety according to Formula (V), (VI) or (VII), and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof.
According to a fifth embodiment, the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor ligand according to the following formula (Formula (V)), pharmaceutically- acceptable salts, hydrates, solvates and/or prodrugs thereof (see International Patent
Application Number PCT/US08/06675 incorporated herein by reference in its entirety):
Figure imgf000041_0001
(V) wherein
X is selected from the group consisting of -CH2-S-S-CH2-, -C(CHa)2-S-S-CH2-, -CH2-S-S-C(CHa)2-, -C(CHs)2-S-S-C(CHs)2-, -(CH2J2-S-S-CH2-, -CH2-S-S-(CH2J2-, -(CH2J2-S-S-(CH2)Z-, -C(CH3)Z-S-S-(CHz)2-, -(CHa)2-S-S-C(CHs)2-, -(CH2).-C(O)-NR8- (CHz)r- and -(CH2),- NR8-C(O)-(CH2), -;
R1 and R2 each is, independently, H, (Ci-Go)alkyl or substituted (d-Cio)alkyl;
R3 is -OH or -NHz; R4 and R5 each is, independently, H, (G-Cio)alkyl or substituted (Ci-Cio)alkyl;
R6 R7
Figure imgf000042_0001
A1 is His, 2-Pal, 3-Pal, 4-Pal, (X\X2,X*,X\X5)Phe, Taz, 2-Thi, 3-Thi or is deleted;
A2 is D-BaI, D-I-NaI, D-2-Nal, D-Phe or D-(X1,X2,X3,X4,X5)Phe;
A3 is Arg, hArg, Dab, Dap, Lys or Orn; A4 is BaI, 1-Nal, 2-Nal, (X1,X2,X3,X4,X5)Phe or Trp;
R6 and R7 each is, independently for each occurrence thereof, H, (Ci-Cio)alkyl, (Ci-Cio)heteroalkyl, aryl(Ci-Cs)alkyl, substituted (Ci-Cio)alkyl, substituted (Ci- Cio)heteroalkyl or substituted aryl(Ci-Cs)alkyl provided that R6 and R7 may be joined together to form a ring; R8 is H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; r is, independently for each occurrence thereof, 1, 2, 3, 4 or 5; and t is, independently for each occurrence thereof, 1 or 2.
Preferrably, a compound according the foregoing fourmula found useful to treat insulin resistance in a mammalian subject, with or without weight loss, include compounds wherein X1 is selected from the group consisting of:
Figure imgf000043_0001
and . Representative embodiments of the foregoing class of compounds useful to treat insulin resistance in a mammalian subject, with or without weight loss, are as follows: c[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:
271) c[Hydantoin(C(O)-(hCys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:271) c[Hydantoin(C(O)-(Cys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH2; (SEQ ID NO:272) or c[Hydantoin(C(O)-(hCys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH2; (SEQ ID NO:272) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:273) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH2; (SEQ ID
NO:273) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH2; (SEQ ID NO:273) or c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH2; (SEQ ID NO:273) c[Hydantoin(C(O)-(Asp-His))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Asp-His))-D-Phe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 274) c[Hydantoir»(C(O)-(Asp-A3c))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-A5c))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-A6c))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-A3c))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Asp-A5c))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Asp-A6c))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Asp-Aic))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-Apc))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Asp-Apc))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin-(C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH2(SEQ ID NO:275) c[Hydantoin-(C(O)-(Asp-Apc))-D-2-Nal-Arg-Trp-Lys]-NH2 (SEQ ID NO:275) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH2; (SEQ ID NO:276) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH2; (SEQ ID
NO:276) or c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH2/ (SEQ ID NO:276) c[Hydantoin(C(O)-(Glu-His))-D-Phe-Arg-Trp-Dap]-NH2 (SEQ ID NO:277) According to a sixth embodiment, the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor compound according to Formula (VI), pharmaceutically-acceptable salts, hydrates, solvates and/or prodrugs thereof (see International Patent Application Number PCT/US08/06675 which is incorporated herein by reference in its entirety):
Figure imgf000044_0001
(VI) wherein
Figure imgf000045_0001
A1 is Asp, Cys, D-Cys, Dab, Dap, GIu, Lys, Orn, Pen or D-Pen; A2 is an L- or D-amino acid;
A3 is His, 2-Pal, 3-Pal, 4-Pal, (X1,X2,X3,X4,X5)Phe, Taz, 2-Thi or 3-Thi;
A4 is D-BaI, D-I-NaI, D-2-Nal, D-Phe or D-(X1,X2,X3,X4,X5)Phe;
A5 is Arg, hArg, Dab, Dap, Lys or Orn;
A6 is BaI, 1-Nal, 2-Nal, (X\X2,X3,X4,X5)Phe or Trp, ; A7 is Asp, Cys, D-Cys, Dab, Dap, GIu, Lys, Orn, Pen or D-Pen;
R1 is H, (Ci-Go)alkyl or substituted (Ci-Go)alkyl;
R2 and R3 each is, independently, H, (G-Cio)alkyl, (Ci-Cio)heteroalkyl, aryl(G- Csjalkyl, substituted (Ci-Go)alkyl, substituted (G-Cio)heteroalkyl or substituted aryl(G-Cs)alkyl or R2 and R3 may be fused together form a cyclic moiety;
Figure imgf000045_0002
R5 and R6 each is, independently, H, (G-Go)alkyl, (G-Go)heteroalkyl, aryl(G- Cs)alkyl, substituted (G-Go)alkyl, substituted (G-Go)heteroalkyl or substituted aryl(G-C5)alkyl or R5 and R6 may be fused together form a cyclic moiety;
R7 and R8 each is, independently, H, (G-Go)alkyl, (G-Go)heteroalkyl, aryl(G- G)alkyl, substituted (G-Go)alkyl, substituted (G-Go)heteroalkyl or substituted aryl(G-C5)alkyl; or R7 and R8 may be fused together form a cyclic moiety;
R9 is H, (G-Go)alkyl or substituted (G-Go)alkyl; and n is, independently for each occurrence thereof, 1, 2, 3, 4, 5, 6 or 7; or a pharmaceutically acceptable salt thereof. A preferred class of compounds according to Formula (VI) useful to treat insulin resistance in a mammalian subject, with or without weight loss, are those compounds wherein:
A1 is Cys; A2 is D-AIa, Asn, Asp, GIn, GIu or D-Phe;
A3 is His;
A4 is D-2-Nal or D-Phe; A5 is Arg; A6 is Trp; and A7 is Cys or Pen; each of R1, R2, R3, and R9 is, independently, H; R4 is C(O)NH2; each of R5 and R6 is, independently, H, (Ci-Cio)alkyl, (Ci-Cio)heteroalkyl, substituted (Ci-Cio)alkyl or substituted (Ci-Cio)heteroalkyl or R5 and R6 may be fused together form a cyclic moiety; and each of R7 and R8 is, independently, H, (Ci-Cio)alkyl, (Ci-Cio)heteroalkyl, substituted (Ci-Cio)alkyl or substituted (Ci-Cio)heteroalkyl; or pharmaceutically acceptable salts thereof.
. Preferred compounds of the immediately foregoing formula (Formula (VI)) useful to treat insulin resistance in a mammalian subject, with or without weight loss, include:
Hydantoin(C(O)-(Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:278)
Hydantoin(C(O)-(Nle-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2, (SEQ ID NO:278)
Hydantoin(C(O)-(Gly-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:278)
Hydantoin(C(O)-(Nle-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2, (SEQ ID NO:279) Hydantoin(C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279) Hydantoin(C(O)-(Nle-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO:280)
Hydantoin(C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO:280) Hydantoin(C(O)-(Ala-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279)
Hydantoin(C(O)-(D-Ala-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279)
Hydantoin(C(O)-(Aib-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279)
Hydantoin(C(O)-(Val-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279)
Hydantoin(C(O)-(Ile-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279) Hydantoin(C(O)-(Leu-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279)
Hydantoin(C(O)-(Gly-Gly))-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO:281)
Hydantoin(C(O)-(Nle-Gly))-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO:281)
Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:278)
Hydantoin(C(O)-(Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:278) Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ
ID NO:279)
Hydantoin(C(O)-(Arg-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279)
Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO:282) Hydantoin(C(O)-(Arg-Gly))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO:282)
Hydantoin(C(O)-(Nle-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:278) Hydantoin(C(O)-(Gly-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ
ID NO:278)
Hydantoin(C(O)-(Nle-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279)
Hydantoin(C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279)
Hydantoin(C(O)-(Nle-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO:280)
Hydantoin(C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID NO:280) Hydantoin(C(O)-(Ala-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279)
Hydantoin(C(O)-(D-Ala-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279)
Hydantoin(C(O)-(Aib-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279)
Hydantoin(C(O)-(Val-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279)
Hydantoin(C(O)-(Ile-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279) Hydantoin(C(O)-(Leu-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279)
Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:278)
Hydantoin(C(O)-(Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:278) Hydantoin(C(O)-(Arg-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279) or
Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279) Hydantoin(C(O)-(Ala-Nle))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ
ID NO:283)
Hydantoin(C(O)-(Val-Nle))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:283)
Hydantoin(C(O)-(Gly-Nle))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:283)
Hydantoin(C(O)-(A6c-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:284)
Hydantoin(C(O)-(Gly-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:284) Hydantoin(C(O)-(Ala-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:284)
Hydantoin(C(O)-(D-Ala-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:284)
Hydantoin(C(O)-(Val-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:284)
Hydantoin(C(O)-(Leu-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:284)
Hydantoin(C(O)-(Cha-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:284)or Hydantoin(C(O)-(Aib-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ
ID NO:284)
Hydantoin(C(O)-(Gly-Arg))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:285)
Hydantoin(C(O)-(Gly-Arg))-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO:285) Hydantoin(C(O)-(Gly-Arg))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:286)
Hydantoin(C(O)-(Gly-Arg))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO:286) Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:287)
Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:287)
Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:288) and
Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO:288)
Hydantoin(C(O)-(Nle-Ala))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO:289); or pharmaceutically acceptable salts thereof.
In a seventh embodiment, the invention provides a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor ligand belonging to a class of cyclic peptide analogs that are ligands for the melanocortin receptors having a structure according to Formula (VII) as depicted below (see International Patent Application Number PCT/US08/06675 which is incorporated herein by reference in its entirety):
Figure imgf000050_0001
(VII) wherein
X is selected from the group consisting of -CH2-S-S-CH2-, -C(CFb)2-S-S-CH2-, -CH2-S-S-C(CHs)2-, -C(CHa)2-S-S-C(CHa)2-, -(CH2J2-S-S-CH2-, -CH2-S-S-(CH2J2, -(CH2)2-S-S-(CH2)2-, -C(CH3)Z-S-S-(CH2J2-, -(CHa)2-S-S-C(CHs)2-, -(CH2)t-C(O)-NR8- (CH2),- and -(CH2)r NR8-C(O)-(CH2)t -; each of R1 and R5 is, independently, H, (Ci-Cio)alkyl or substituted (Ci-Cio)alkyl; each of R2 and R3 is, independently, H, (G-Cio)alkyl, (Ci-Cio)heteroalkyl, aryl(Ci-C5)alkyl, substituted (Ci-Cio)alkyl, substituted (Ci-Cio)heteroalkyl or substituted aryl(Ci-C5)alkyl or R2 and R3 may be fused together to form a ring; R4 is OH or NH2; each of R6 and R7 is, independently, H, (Ci-Cio)alkyl or substituted (Ci- Cio)alkyl;
A1 is an L- or D-amino acid or deleted;
A2 is His, 2-Pal, 3-Pal, 4-Pal, (X'^X^X^X^Phe, Taz, 2-Thi or 3-Thi; A3 is D-BaI, D-I-NaI, D-2-Nal, D-Phe or D-(X\X2,X3,X4,X5)Phe; A4 is Arg, hArg, Dab, Dap, Lys or Orn,; A5 is BaI, 1-Nal, 2-Nal, (X'^X^X^Phe or Trp,; r is, independently for each occurrence thereof, 1, 2, 3, 4 or 5; and t is, independently for each occurrence thereof, 1 or 2; or pharmaceutically acceptable salts thereof.
In the preferred aspect of the compounds according to Formula (VII) useful to treat insulin resistance in a mammalian subject, with or without weight loss,
A1 is Ala, D-AIa, Asn, Asp, GIn, GIu or GIy; or pharmaceutically acceptable salts thereof.
Preferred compounds according to Formula (VII) useful in the treatment of insulin resistance in a mammalian subject, include the following compounds: c[Hydantoin(C(O)-(Nle-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID
NO:290) c[Hydantoin(C(O)-(Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(D-Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(Aib-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ lD NO:290) c[Hydantoin(C(O)-(Val-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(Abu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID
NO:290) c[Hydantoin(C(O)-(Leu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(Ile-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(Cha-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(A6c-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(Phe-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID
NO:290) c[Hydantoin(C(O)-(Gly-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) or c[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:291) or c[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH2 (SEQ ID NO:291); or pharmaceutically acceptable salts thereof.
In an eighth embodiment, the present invention is directed to a method to treat insulin resistance in a mammalian subject, with or without weight loss, by the administration of a therapeutically effective amount of a melanocortin receptor ligand according to Formula (VIII) (see International Patent Application Number
PCT/US08/07411, incorporated herein by reference in its entirety):
(R2R3)- A°-Al-c(A2-A3-A4-A5-A6-A7-A8-A9)-Al0-R1
(VIII) wherein: A0 is an aromatic amino acid
A1 is Ace, HN-(CH2)m-C(O), an L- or D-amino acid;
A2 is Asp, Cys, D-Cys, hCys, D-hCys, GIu, Pen, or D-Pen;
A3 is Aib, Ala, β-Pύa, Gaba, GIy or a D-amino acid; A4 is His, 2-Pal, 3-Pal, 4-Pal, (X'^X^X^Phe, Taz, 2-Thi, or 3-Thi;
A5 is D-BaI, D-I-NaI, D-2-Nal, D-Phe, L-Phe, D-(X1,X2,X3,X4,X5)Phe, L-Phe, D-Trp or D-(Et)Tyr;
A6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH((CH2)n-N(R4R5))-C(O);
A7 is BaI, D-BaI, Bip, D-Bip, 1-Nal, D-I-NaI, 2-Nal, D-2-Nal, or D-Trp; A8 is Ace, Aha, Ahx, Ala, D-AIa, β-Ala, Apn, Gaba, GIy, HN-(CH2)S-C(O), or deleted;
A9 is Cys, D-Cys, hCys, D-hCys, Dab, Dap, Lys, Orn, Pen, or D-Pen;
A10 is Ace, HN-(CH2)t-C(O), L- or D-amino acid, or deleted;
R1 is OH, or NH2; each of R2 and R3 is, independently for each occurrence selected from the group consisting of H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (G-C3o)acyl, (C2-C3o)alkenyl, (C2-C3o)alkynyl, aryl(G-C3o)alkyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)alkyl, substituted (Ci-C3o)heteroalkyl, substituted (Ci-C3o)acyl, substituted (C2-C3o)alkenyl, substituted (C2-C3o)alkynyl, substituted aryl(Ci-C3o)alkyl, and substituted aryl(Ci-
each of R4 and R5 is, independently for each occurrence, H, (Ci-G«))alkyl, (Ci-
Cwjheteroalkyl, (Ci-C4o)acyl, (C2-Gκ))alkenyl, (C2-C4o)alkynyl, aryl(Ci-C4o)alkyl, aryl(Ci-C4o)acyl, substituted (Ci-C4o)alkyl, substituted (Ci-C4o)heteroalkyl, substituted
(Ci-C4o)acyl, substituted (Q-C4o)alkenyl, substituted (C2-C4o)alkynyl, substituted aryl(Ci-C4o)alkyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl, or -C(NH)-NH2; m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; n is, independently for each occurrence, 1, 2, 3, 4 or 5; s is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; t is, independently for each occurrence, 1, 2, 3, 4, 5, 6, or 7; X1, X2, X3, X4, and X5 each is, independently for each occurrence, H, F, Cl, Br, I,
(Ci-io)alkyl, substituted (Ci-io)alkyl, (C2-io)alkenyl, substituted (C2-io)alkenyl, (CMo)alkynyl, substituted (C2-io)alkynyl, aryl, substituted aryl, OH, NH2, NOz, or CN; provided that
(I). when R4 is (Ci-C4o)acyl, aryl(Ci-C4o)acyl, substituted (Ci-C4o)acyl, substituted aryl(Ci-C4o)acyl, (Ci-C4o)alkylsulfonyl, or -C(NH)-NH2, then R5 is H or (Ci-Gio)alkyl, (Ci-C4o)heteroalkyl, (C2-C»o)alkenyl, (C2-C4o)alkynyl, aryl(G- C4o)alkyl, substituted (Ci-Cto)alkyl, substituted (Ci-C4o)heteroalkyl, substituted (C2- C4o)alkenyl, substituted (C2-C4o)alkynyl, or substituted aryl(Ci-G«))alkyl;
(II). when R2 is (Ci-Owjacyl, aryl(Ci-C3o)acyl, substituted (Ci-C3o)acyl, or substituted aryl(Ci-C3o)acyl, then R3 is H, (Ci-C3o)alkyl, (Ci-C3o)heteroalkyl, (C2- Csojalkenyl, (C2-C3o)alkynyl, aryl(Ci-C3o)alkyl, substituted (Ci-C3o)alkyl, substituted
(Ci-C3o)heteroalkyl, substituted (C2-C3o)alkenyl, substituted (C2- C3o)alkynyl, or substituted aryl(Ci-C3o)alkyl;
(III). when A2 is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen, then A9 is Cys, D-Cys, hCys, D-hCys, Pen, or D-Pen; (IV). when A2 is Asp or GIu, then A9 is Dab, Dap, Orn, or Ly s;
(V). when A8 is Ala or GIy, then A1 is not NIe; or pharmaceutically acceptable salts thereof.
A preferred group of compounds of the immediate foregoing formula useful to treat insulin resistance in a mammalian subject, with or without weight loss, is wherein
A0 is 1-Nal, 2-Nal, His, Pff, Phe, Trp, or Tyr;
A1 is Arg;
A2 is Cys;
A3 is D-AIa; A4 is His;
Figure imgf000054_0001
A6 is Arg;
A8 is deleted; A9 is Cys; and
A10 is deleted; or pharmaceutically acceptable salts thereof.
Preferred compounds of the immediately foregoing group of compounds is which are useful to treat insulin resistance in a mammalian subject, with or without weight loss, of the formula: Ac-Tyr-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-2-NaI-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-l-Nal-Arg-c(Cys-D-Ala-His-DPhe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-Phe-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-Trp-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-Pff-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292)
H-His-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:293) or Ac-His- Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) or pharmaceutically acceptable salts thereof.
In yet another preferred embodiment, the compound or compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) as defined hereinabove, which are useful to treat insulin resistance in a mammalian subject, with or without weight loss, or a pharmaceutically acceptable salt thereof, are provided to said subject in need in a composition with a pharmaceutically acceptable carrier or diluent.
In preferred embodiment, the invention provides a method of treating insulin resistance in a subject in need thereof, comprising peripheral administration of an effective amount of a melanocorrin receptor 4 agonist to treat the insulin resistance in the subject in need thereof.
In one aspect, the melanocorrin receptor 4 agonist useful to treat insulin resistance with or without an accompanying reduction in body weight in the subject in need thereof, is selected from the group consisting of:
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-J?-Ala-Lys)-NH2; SEQ ID NO:1 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH2; SEQ ID NO:1 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp- Ahx-Cys)-NH2; SEQ ID NO:2 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2; SEQ ID NO:3 D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH2; SEQ ID NO:3 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2; SEQ ID NO:3 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:2 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2; SEQ ID NO:4 Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:5 Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6 Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 Ac-Nle-c(Cys- Aib-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 Ac-Nle-c(D-Cys- Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8 Ac-Nle-c(D-Cys-D- Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8 Ac-Nle-c(D-Cys-/- Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8 Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8 Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8 Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8 Ac-Nle-c(Cys-D- Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9 Ac-Nle-c(Cys-/- Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9 Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9 Ac-Nle-c(Cys- Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9 Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9 Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10 Ac-Nle-c(D-Cys-D- Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10 Ac-Nle-c(D-Cys-/-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10 Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10 Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10 Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11 Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11 Ac-hLeu-cCAsp-His-D-Phe-Arg-Trp-Gaba-Ly S)-NH2; SEQ ID NO: 11 Ac-Phe-cCAsp-His-D-Phe- Arg-Trp-Gaba-Lys^NH^ SEQ ID NO:11 Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 n-butanoyl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:12 Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Ly S)-NH2; SEQ ID NO: 11 Ac-^-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Ly S)-NH2; SEQ ID NO: 11 Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11 Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13 Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13 Ac-Leu-cCAsp-His-D-Phe-Arg-D-Trp-Ala-LysJ-NH∑; SEQ ID NO:13 Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13 Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH2; SEQ ID NO:14 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-_/3-Ala-Lys)-NH2; SEQ ID NO:14 Ac-Nle-cCAsp-His-D-Phe-Arg-D-Trp-Gaba-LysJ-NH∑; SEQ ID NO:14 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH2; SEQ ID NO:14 Ac-Nle-cCAsp-His-D-Phe-Arg-D-Trp-Apn-LysJ-NH^ SEQ ID NO: 14 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH2; SEQ ID NO:15 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH2; SEQ ID NO:15 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH2; SEQ ID NO:15 Ac-Nle-c(Cys-His-D-Phe-Arg-D-TrP:/?-Ala-Cys)-NH2; SEQ ID NO:15 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH2; SEQ ID NO:15 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH2; SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-l-Nal-Cys)-NH2; SEQ ID NO:16 n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO:17 n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:17 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO:18 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-l-Nal-Cys)-NH2; SEQ ID NO:18 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH2; SEQ ID NO:18 Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:61 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH2; SEQ ID NO: 19 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2; SEQ ID NO:20 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:21 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22 D-Phe-c(Cys-His-D-Phe-hArg-Trp-^Ala-D-Cys)-Thr-NH2; SEQ ID NO:23 D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp->Ala-D-Cys)-Thr-NH2; SEQ ID NO:24 D-Phe-c(Cys-His-D-Phe-Arg-Bip-/?-Ala-D-Cys)-Thr-NH2; SEQ ID NO:25 D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-^-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24 D-Phe-c(Cys-His-D-Phe-hArg-Bip-j?-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26 D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip->Ala-D-Cys)-Thr-NH2; SEQ ID NO:26 Nle-c(Cys-His-D-Phe-Arg-Trp- Apn-Cys)-NH2; SEQ ID NO:27
Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2; SEQ ID NO:28 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2; SEQ ID NO:28 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; SEQ ID NO:29 Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:31 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32 Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32 Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH-; SEQ ID NO:33 Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34 Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34 Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:35 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:36 Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH2; SEQ ID NO:37 Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH2; SEQ ID NO:38 Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH2; SEQ ID NO:38 Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:39 Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO:39 Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40 Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-/-Ala-Lys)-OH; SEQ ID NO:41 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp- Ahx-Cys)-OH; SEQ ID NO:42
D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH; SEQ ID NO:43 D-Phe-c(Cys-His-D-Phe-Arg-Trp-/-Ala-D-Cys)-Thr-OH; SEQ ID NO:43 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH; SEQ ID NO:43 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH; SEQ ID NO:42 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH; SEQ ID NO:41 Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH; SEQ ID NO:45 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH; SEQ ID NO:45 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-OH; SEQ ID NO:45 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D- Ala-Cys)-OH; SEQ ID NO:45 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH; SEQ ID NO:46 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH; SEQ ID NO:46 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-l-Nal-Cys)-OH; SEQ ID NO:46 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH; SEQ ID NO:46 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:47 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH; SEQ ID NO:48 Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:50 Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:50 Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:51 Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:52 Ac-Arg-cCCys-His-D-Phe-Arg-Trp-Gaba-PerO-NΗ; SEQ ID NO:52 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:51 Ac-D-Arg-cCAsp-His-D-Phe-Arg-Trp- AIa-LyS)-NH2; SEQ ID NO:53 Ac- Arg-c(Asp-His-D-Phe-Arg-Trp- AIa-LyS)-NH2; SEQ ID NO:53
Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:35 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH2; SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH2; SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-/-Ala-Cys)-NH2; SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:54 Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:55 Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2; SEQ ID NO:55 Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:56 Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal- Ala-Cys)-NH2; SEQ ID NO:56 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp- AIa-CyS)-NH2; SEQ ID NO:57 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-j?-Ala-Cys)-NH2; SEQ ID NO:57 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH2,- SEQ ID NO:58 Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-NH2; (SEQ ID NO:60) Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-Doc-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-
NHz; (SEQ ID NO:61)
Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-^-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-
Figure imgf000061_0001
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys):/?-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-
(Arg)3-NH2; (SEQ ID NO:62)
Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-
NH2; (SEQ ID NO:63)
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Pro)2-Lys-Asp-Tyr-Gly-Arg-(Lys)2-(Arg)2- Gln-(Arg)3-NH2; (SEQ ID NO:64)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Gly-Cys)-(Pro)2-Lys-Asp-Tyr-Gly-Arg-(Lys)2-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:65)
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(^-Ala)2-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-
(AFg)3-NH2; (SEQ ID NO66) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Pro)2-Lys-Asp-Doc-Tyr-Gly-Arg-(Lys)2-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:67)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Gly-Cys)-(Pro)2-Lys-Asp-Doc-Tyr-Gly-Arg-
(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:68)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg- (Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:69)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-Doc-Tyr-Gly-Arg-
(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:69)
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-
(Arg)3-NH2; (SEQ ID NO:70) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-
(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:71)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:72)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Gly-(Arg)5-Gln- (AFg)3-NH2; (SEQ ID NO:73) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)3-NH2; (SEQ ID NO:74)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-Arg-
(Lys)2-Arg-Gln-(Arg)4-NH2; (SEQ ID NO:75) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-Arg-
(Lys)2-Gln-(Arg)5-NH2; (SEQ ID NO:76)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-
Lys-GIn-Lys-(Arg)s-NH2; (SEQ ID NO:77)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-Arg- (Lys)2-(Arg)4-Gln-Arg-NH2; (SEQ ID NO:78)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Aib-Arg-
(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:79)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:80) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:80)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-(Arg)6-Gln-
(AFg)3-NH2; (SEQ ID NO:81)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-(Arg)5-Gln- (AFg)3-NH2; (SEQ ID NO:82)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-(Arg)5-Gln-
(AFg)3-NH2; (SEQ ID NO:82)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?- AIa-(AFg)6-GIn-
(AFg)3-NH2; (SEQ ID NO:81) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-J?-Ala-(Arg)6-Gln-
(AFg)3-NH2; (SEQ ID NO:83)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp->Ala-(Arg)5-Gln-
(AFg)3-NH2; (SEQ ID NO:84)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys- ASp-^-AIa-(AFg)6-GIn- (AFg)3-NH2; (SEQ ID NO:83) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-Arg- (Lys)2-(Arg)3-Gln-(Arg)2-NH2; (SEQ ID NO:85)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg- Gln-(Lys)2-(Arg)5-NH2; (SEQ ID NO:86) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg- (Lys)2-(Arg)5-GIn-NH_; (SEQ ID NO:87)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg- (Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:71)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-/?-Ala-Tyr-Gly-Arg- (Lys)2-( Arg)2-Gln-( Arg)3-NH2; (SEQ ID NO:71 )
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala- (Arg)2-Lys-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:88)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Arg-Lys-
(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:89)
Figure imgf000063_0001
(Arg)2-Lys-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:88)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)2-
Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:90)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Gly-(Arg)2-Lys- (Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:91)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Gly-Arg-Lys-
(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:92)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Tyr-Gly-(Arg)2-
Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:95) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-
Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:96)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Gly-(Arg)2-Lys-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:97)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Gly-Arg-Lys- (Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:92) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-(Arg)2-Lys-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:98)
Ac-c(Cys-GIu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Arg-Lys-
(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:99) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-Arg-
Lys-(Arg)3-GLn-(Arg)3-NH2; (SEQ ID NO:101)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala- (Arg)2-Lys-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:104)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Arg-Lys-(Arg)3- Gln-(Arg)3-NH2; (SEQ ID NO:105)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)2-
Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO: 100)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-Lys-
(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:101) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Gly-(Arg)2-Lys-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:102)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Gly-Arg-Lys-
(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:103)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-(Arg)5-Gln- (Arg)3-NH2; (SEQ ID NO:113)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp-^-Ala-(Arg)5-Gln-
(AFg)3-NH2; (SEQ ID NO:113)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)s-
GIn-(AFg)3-NH2; (SEQ ID NO:114) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp-^-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)3-NH2; (SEQ ID NO:114)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:115)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-(Arg)5-Gln- (Arg)4-NH2; (SEQ ID NO:115) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-(Arg)5-
GIn-(AFg)4-NH2; (SEQ ID NO:116)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-Tyr-Gly-(Arg)5-
GIn-(AFg)4-NH2; (SEQ ID NO:116) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:118)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp-^-Ala-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:118)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp-/-Ala-(Arg)6-Gln- (Arg)3-NH2; (SEQ ID NO:119)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)3-NH2; (SEQ ID NO: 120)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp-/?-Ala-Tyr-Gly-
(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:120) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-j?-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)4-NH2; (SEQ ID NO:121)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-Tyr-Gly-
(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:121)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Tyr-Gly-(Arg)6- GIn-(AFg)3-NH2; (SEQ ID NO:122)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-Tyr-Gly-
(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO:122)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-j?-Ala-(Arg)6-Gln-
(Arg)3-NH2; (SEQ ID NO:124) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:125)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-(Arg)5-Glri-
(AFg)4-NH2; (SEQ ID NO:125)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/?-Ala-Tyr-Gly-(Arg)5- GIn-(AFg)3-NH2; (SEQ ID NO:126) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-Tyr-Gly-
(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:126)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)6-
GIn-(AFg)3-NH2; (SEQ ID NO:127) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp->Ala-Tyr-Gly-
(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO:127)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)4-NH2; (SEQ ID NO:128)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-/?-Ala-Tyr-Gly- (Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:128)
Figure imgf000066_0001
(Arg)4-NH2; (SEQ ID NO:130)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-/-Ala-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:130) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-^-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)3-NH2; (SEQ ID NO:133)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)4-NH2; (SEQ ID NO:134)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-Tyr-Gly-(Arg)5- GIn-(AFg)4-NH2; (SEQ ID NO:134)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)6-
GIn-(AFg)3-NH2; (SEQ ID NO:135)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-^-Ala-Tyr-Gly-(Arg)6-
GIn-(AFg)3-NH2; (SEQ ID NO:135) Ac-NIe-C(CyS-D-AIa-HiS-D-PHe-AFg-TFp-CyS)-(DoC)2-TyF-GIy-AFg-(LyS)2-(AFg)2-GIn-
(AFg)3-NH2; (SEQ ID NO:136)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-/-Ala-Tyr-Gly-Arg-(Lys)2-Arg-Gln-
(AFg)4-NH2; (SEQ ID NO:137)
Ac-NIe-C(CyS-D-AIa-HiS-D-PHe-AFg-TFp-CyS)-DoC-TyF-GIy-AFg-(LyS)2-(AFg)2-GIn- (AFg)3-NH2; (SEQ ID NO:136) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:138)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-J?-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:138) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:139)
Ac-Nle-c(Cys-D- Ala-His-D-Phe-Arg-Trp-Cys)-^-Ala-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:140)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys):/?-Ala-Tyr-Gly-(Arg)2-Lys-(Arg)2-Gln- (Arg)3-NH2; (SEQ ID NO:141)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-^-Ala-Tyr-Gly-Arg-Lys-(Arg)3-Gln-
(Arg)3-NH2; (SEQ ID NO:142)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-^-Ala-Gly-(Arg)2-Lys-(Arg)2-Gln-
(Arg)3-NH2; (SEQ ID NO:141) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys):/?-Ala-Gly-Arg-Lys-(Arg)3-Glii-(Arg)3-
NH2; (SEQ ID NO:142)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys):/?-Ala- (Arg)2-Lys-(Arg)2-Gln-(Arg)3-
NH2; (SEQ ID NO:143)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-^-Ala-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:144)
Ac-Nle-c(Cys-D- Ala-His-D-Phe-Arg-Trp-Cys)->Ala- (Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:148)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(^-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:148) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(^-Ala)2-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:149);
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:149)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:151) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:150)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:150) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:151)
Ac-Nle-c(Cys-D- Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:152)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:152)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys):/?-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:154)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:153) Ac-Nle-c(Cys-D- Ala-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO: 154)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO: 155)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4- NH2; (SEQ ID NO: 155)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:157)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:156) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:156)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)s-Gln-(Arg)4-NH2; (SEQ
ID NO:157)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:158) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:158)
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:159) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:160)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:161)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:162)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:164)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-/-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:163) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:163)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:164)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(^-Ala)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:165)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(^-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:165)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:166) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:166)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:168)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:167) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:167)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:168) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:170)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys):/?-Ala-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:169)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-^-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:169)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO: 170)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(/?-Ala)2-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:171) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(^-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:171)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2, (SEQ ID
NO:173)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Gly-(Arg)s-Gln-(Arg)4-NH2; (SEQ ID NO:172)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-(Arg)5-Gln-(Arg)4-NH2, (SEQ ID
NO:172)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:173) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO: 174)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:174)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-/?-Ala-Lys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:175) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-^-Ala-Lys)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:176)
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:177) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-j?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO: 178)
D-Phe-c(Cys-His-D-Phe-Arg-Trp:/?-Ala-D-Cys)-Thr:/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:179)
D-Phe-c(Cys-His-D-Phe-Arg-Trp-^-Ala-D-Cys)-Thr-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:180)
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:181)
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:182) Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:183)
Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:184)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO.183)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:185)
Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:186) Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:185)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:186)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:188) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:187)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(^-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:188) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:189)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:190)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3- NH2; (SEQ ID NO:189)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:190)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:191) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:192)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(^-Ala)2-Tyr-Gly-(Arg)s-Gln-(Arg)4-
NH2; (SEQ ID NO:191)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(^-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:192)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:193)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:194) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:193)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:194)
Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3- NH2; (SEQ ID NO:195) Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:196)
Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-j?-Ala-Tyr-Gly-(Arg)s-Gln-(Arg)3-NH2;
(SEQ ID NO:197) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:198)
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:199)
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-JJ-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:200)
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:199)
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:200) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-/?-Ala-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:201)
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-^-Ala-Cys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:202)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:203)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen):/?-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:203)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:205) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:204)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(/?-Ala)2-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:204)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(^-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:205) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:207)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:206) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:206)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:207)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(Doc)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:208)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:208)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-^-Ala-D-Cys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:209) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-/-Ala-D-Cys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:210)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys):/?-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:209)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-TrP:/?-Ala-D-Cys)-/?-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:211)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-/-Ala-D-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-
(AFg)3-NH2; (SEQ ID NO:212)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-TrP:/?-Ala-D-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:213) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-/-Ala-D-Cys)-(/?-Ala)2-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:213)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys)-(^-Ala)2-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:267)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-TrP:/?-Ala-D-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3- NH2; (SEQ ID NO:214) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-TrP:/?-Ala-D-Cys)-Doc-(Arg)5-Glii-(Arg)3-NH2; (SEQ
ID NO:216)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:214) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-/?-Ala-D-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:217)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-^-Ala-D-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:215)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-TrP:/?-Ala-D-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:216)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-/-Ala-D-Cys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:215)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:217) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr:/?-Ala-Tyr-Gly-(Arg)5-Gbi-
(AFg)3-NH2; (SEQ ID NO:218)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr-/-Ala-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:219)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-TrP:/?-Ala-D-Cys)-Thr-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln- (Arg)3-NH2; (SEQ ID NO:218)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-TrP:/?-Ala-D-Cys)-Thr-(^-Ala)2-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:219)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:221) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr-Doc-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:220)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-/-Ala-D-Cys)-Thr-(Doc)2-Tyr-Gly-(Arg)5-Glrι-
(AFg)3-NH2; (SEQ ID NO:221)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-TrP:/?-Ala-D-Cys)-Thr-^-Ala-Tyr-Gly-(Arg)5-Gln- (Arg)4-NH2; (SEQ ID NO:222) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-/?-Ala-D-Cys)-Thr-j?-Ala-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:223)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-/-Ala-D-Cys)-Thr-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:222) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-/?-Ala-D-Cys)-Thr-(/?-Ala)2-(Arg)5-Gln-(Arg)4-
Figure imgf000076_0001
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-^-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln-
(ATg)4-NH2; (SEQ ID NO:224)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:225)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-/-Ala-D-Cys)-Thr-(Doc)2-Tyr-Gly-(Arg)5-Gln-
(AFg)4-NH2; (SEQ ID NO:224)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-^-Ala-D-Cys)-Thr-(Doc)2-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:225) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-/-Ala-D-Cys)-Thr-/-Ala-Tyr-Gly-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:227)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip:/?-Ala-D-Cys)-Thr-^-Ala-Tyr-Gly-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:226)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-^-Ala-D-Cys)-Thr-/-Ala-(Arg)5-Gln-(Arg)3- NH2; (SEQ ID NO:228)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-^-Ala-D-Cys)-Thr-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:227)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-^-Ala-D-Cys)-Thr-(/?-Ala)2-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:228) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip:/?-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:229)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip:/?-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:230)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-^-Ala-D-Cys)-Thr-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:232) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-j8-Ala-D-Cys)-Thr-(Doc)2-Tyr-Gly-(Arg)5-Gln-
(AFg)3-NH2; (SEQ ID NO:231)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip:/?-Ala-D-Cys)-Thr-(Doc)2-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:232) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:233)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)->Ala-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:234)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-^-Ala-Tyr-Gly-(Arg)s-Gln-(Arg)3-NH2; (SEQ ID NO:235)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:236)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:235) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(^-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:236)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:237)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-/-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:238)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:237)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(^-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:238) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:239)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:240)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Glri-(Arg)3-NH2; (SEQ ID NO:239) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2, (SEQ ID
NO:240)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:241) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:242)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:241)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:242)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:243)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:244) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:243)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:244)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)s-Gln-(Arg)3-NH2; (SEQ ID NO:245)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)s-Gln-(Arg)3-NH2; (SEQ ID
NO:246)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:245) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:246)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-j?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:247)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys):/?-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:248) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-
Figure imgf000079_0001
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:248) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:249)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:250)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4- NH2; (SEQ ID NO:249)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:250)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:251) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-^-Ala-(Arg)s-Gln-(Arg)3-NH2; (SEQ ID
NO:252)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:251)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:252)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:253)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:254) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:253)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:254)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:255) Ac-Nle-cCCys-D-Cha-His-D-Phe-Arg-Trp-CysJ-^-Ala-CArgJs-Gln-CArgJ^NH^ CSEQ ID
NO:256)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:255) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(^-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:256)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:257)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:258)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:257)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO.258) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:259)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys):/?-Ala-(Arg)5-Glii-(Arg)3-NH2; (SEQ ID
NO:260)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:259)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:260)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:261) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-/-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:262)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(/f-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:261)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:262) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:263)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:264) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:263)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:264)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:265)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:266)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:265) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:266)
Ac-c(Cys-Glu-His-D-4-Br-Phe-Arg-Trp-Gly-Cys)-(Pro)2-Lys-Asp-NH2, (SEQ ID
NO:268)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys- Asp-NH2; (SEQ ID NO:269) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys- Asp-NH2; (SEQ ID
NO:269)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID
NO:269)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID NO:269) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-^-Ala-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID
NO:270)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Aib-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID
NO:270) c[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:271) c[Hydantoin(C(O)-(hCys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:271) c[Hydantoiri(C(O)-(Cys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH2; (SEQ ID NO:272) c[Hydantoin(C(O)-(hCys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH2; (SEQ ID NO:272) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:273) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH2; (SEQ ID NO:273) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH2; (SEQ ID NO:273) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH2; (SEQ ID NO:273) c[Hydantoin(C(O)-(Asp-His))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Asp-His))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-A3c))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-A5c))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-A6c))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-A3c))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Asp-A5c))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Asp-A6c))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin (C(O)-(Asp-A5c))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Asp-Aic))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-Apc))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Asp-Apc))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin-(C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin-(C(O)-(Asp-Apc))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH2; (SEQ ID NO:276) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH2; (SEQ ID NO:276) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH2; (SEQ ID NO:276) c[Hydantoin(C(O)-(Glu-His))-D-Phe-Arg-Trp-Dap]-NH2; (SEQ ID NO:277) Hydantoin(C(O)-(Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:278)
Hydantoin(C(O)-(Nle-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:278) Hydantoin(C(O)-(Gly-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:278) Hydantoin(C(O)-(Nle-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279)
Hydantoin(C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279) Hydantoin(C(O)-(Nle-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID
NO:280)
Hydantoin(C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2, (SEQ ID
NO:280)
Hydantoin(C(O)-(Ala-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279)
Hydantoin(C(O)-(D-Ala-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279)
Hydantoin(C(O)-(Aib-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279) Hydantoin(C(O)-(Val-Gly))-c(CysrD-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279)
Hydantoin(C(O)-(Ile-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279)
Hydantoin(C(O)-(Leu-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279) Hydantoin(C(O)-(Gly-Gly))-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID
NO:281)
Hydantoin(C(O)-(Nle-Gly))-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID
NO.-281)
Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO.-278)
Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279)
Hydantoin(C(O)-(Arg-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279) Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID
NO:282) Hydantoin(C(O)-(Arg-Gly))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID
NO:282)
Hydantoin(C(O)-(Ala-Nle))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ro
NO:283) Hydantoin(C(O)-(Val-Nle))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:283)
Hydantoin(C(O)-(Gly-Nle))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:283)
Hydantoin(C(O)-(A6c-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:284)
Hydantoin(C(O)-(Gly-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:284)
Hydantoin(C(O)-(Ala-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:284) Hydantoin(C(O)-(D-Ala-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:284)
Hydantoin(C(O)-(Val-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:284)
Hydantoin(C(O)-(Leu-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:284)
Hydantoήi(C(O)-(Cha-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:284)
Hydantoin(C(O)-(Aib-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:284) Hydantoin(C(O)-(Gly-Arg))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:285)
Hydantoin(C(O)-(Gly-Arg))-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID
NO:285)
Hydantoin(C(O)-(Gly-Arg))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:286) Hydantom(C(O)-(Gly-Arg))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID
NO:286)
Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2, (SEQ ID
NO:287) Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:288)
Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID
NO:288)
Hydantoin(C(O)-(Nle-Ala))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:289) c[Hydantoin(C(O)-(Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2/ (SEQ ID NO:290) c[Hydantoin(C(O)-(Nle-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(D-Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID
NO:290) c[Hydantoin(C(O)-(Aib-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID
NO:290) c[Hydantoin(C(O)-(Val-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(Abu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID
NO:290) c[Hydantoin(C(O)-(Leu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID
NO:290) c[Hydantoin(C(O)-(Ile-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantom(C(O)-(Cha-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2, (SEQ ID
NO:290) c[Hydantoin(C(O)-(A6c-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID
NO:290) c[Hydantoin(C(O)-(Phe-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID
NO:290) c[Hydantoin(C(O)-(Gly-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:291)
Ac-Tyr-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-2-Nal-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-l-Nal-Arg-c(Cys-D-Ala-His-DPhe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-Phe-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-Trp-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-Pff-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292)
H-His- Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:293) and Ac-His-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) or a pharmaceutically acceptable salt thereof.
In one preferred aspect, the melanocortin receptor 4 agonist useful to treat insulin resistance in the subject in need thereof, is Ac-Arg-c(Cys-D-Ala-His-D-Phe- Arg-Trp-Cys)-NH2 (SEQ ID NO:50) or a pharmaceutically acceptable salt thereof. In another preferred aspect, the melanocortin receptor 4 agonist useful to treat insulin resistance in the subject in need thereof, is Hydantoin(C(O)-(Arg-Gly))-c(Cys-Glu- His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO:278) or a pharmaceutically acceptable salt thereof.
In other aspects of the invention, administration of a compound or compostion comprising a compound or pharmaceutical salt of a compound of the invention useful to treat insulin resistance, is continuous, hourly, four times daily, three time daily, twice daily, once daily, once every other day, twice weekly, once weekly, once every two weeks, once a month, or once every two months, or longer.
The subject in need of treatment may be obese, overweight, of normal weight or lean. The obese, overweight, normal weight or lean subject may suffer from type II diabetes. The preferred administration of a compound or compostion comprising a compound or pharmaceutical salt of a compound of the invention useful to treat insulin resistance, is peripheral administration. Examples of peripheral administration include oral, subcutaneous, intraperitoneal, intramuscular, intravenous, rectal, transdermal or intranasal forms of administration.
BRIEF DESCRIPTION OF THE DRAWINGS: Figure 1: Food consumed in fasted rats 6 hours after administration of 100 nmole/Kg of selected compounds.
Figure 2. Effect of subcutaneous administration of 75, 300 or 600 nmole/kg/day of Compound A upon (A) body weight, (B) cumulative food intake, (C) insulin levels and (D) glucose levels in rats.
Figure 3. Effect of subcutaneous administration of 75, 300 or 600 nmole/kg/day of Compound B upon (A) body weight, (B) cumulative food intake, (C) insulin levels and (D) glucose levels in rats.
Figure 4. Effect of subcutaneous administration of 200, 600 or 1800 nmole/kg/day of Compound A upon blood glucose levels in mice.
Figure 5. Effect of intraperitoneal administration of 6.4 μmole/kg of Compound A upon blood glucose levels in obese mice. DETAILED DESCRIPTION OF THE INVENTION
Recent studies have reported that staggering numbers of people world wide are overweight and suffering a wide variety of serious and expensive health problems. According the World Health Organization (as reported in Kouris-Blazos et al, Asia Pac. J. Clin. Nutr., 2007, 16:329-338), an estimated 1 billion people throughout the world are overweight and an estimated 300 million of these are obese. An estimated 22 million children under the age of 5 are severely overweight and in the European Union alone, the number of children who are overweight is expected to rise by 1.3 million children per year (Kosti et al, 2006, Cent. Eur. J. Public Health, 14:151-159). Obesity, as defined by the Statistical Bulletin provided by the Metropolitan Life Insurance Co., (1959, 40:1), is a condition in which a person is approximately 20-25% over normal body weight. Alternatively, an individual is considered obese if the person has a body mass index of greater than 25% over normal or greater than 30% over normal with risk factors (see Bray et al, Diabetes/Metabolism Review, 1988, 4:653-679 or Flynn et al., Proc. Nutritional Society, 1991, 50:413). One of the main causes for obesity is the consumption of a high caloric diet (Riccardi et al, Clin. Nutr., 2004, 23:447-456).
Diabetes is a chronic, debilitating disease afflicting many overweight and obese people. It is estimated that 20.8 million people in the United States alone have diabetes and more than 6 million more additional cases remain undiagnosed (Cornell, Manag. Care Pharm., 2007, 13:Sll-5). Type 2 diabetes (also referred to herein as type II diabetes) is a chronic disease characterized by insulin resistance, impaired insulin secretion and hyperglycemia. Worldwide, type II diabetes is believed to affect approximately 171 million people, imparting numerous microvascular and macrovascular complications resulting in morbidity and mortality (Mudaliar, Indian J. Med. Res., 2007, 125:275-296). Mudaliar further notes that despite the availability of anti-hyperglycaemic agents available, control of glucose remains elusive in many patients.
Insulin resistance, also referred to as reduced insulin sensitivity, is a condition in which the amount of insulin needed to clear glucose from the blood of a subject is increased as compared to the amount of insulin needed to clear the same amount of glucose from the blood of a normal, non-insulin sensitive subject. Insulin resistance is regarded as the main link between obesity and type II diabetes (see Obici et al, J. Clin. Inv., 2001, 108:1079-1085 and references therein). It is known that rats fed a high fat diet show an increase in body weight (diet-induced obesity or DIO) and a decrease in insulin sensitivity. Such DIO rats provide an animal model in which to study the mechanisms of insulin resistance due to obesity (see for example Banno et al, FEBS letters, 2007, 581:1131-1136). The size and weight of adipose tissues are increased in DIO rats and it is thought that the accompanying hypertrophy of adipocytes leads to changes in the release of adipocytokines such as leptin and adiponectin which are known to regulate insulin sensitivity; it is thought that morphological changes in adipose tissue as well as changes in plasma levels of adipocytokines are among the causes of insulin resistance in DIO rats (summarized in Banno, et al., FEBS letters, 2007, 581:1131-1136 and references therein).
Melanocortins are proposed to play a large role in energy metabolism and homeostasis. Melanocortins cleaved from the POMC precursor exert their effects by binding to members of the melanocortin receptor family located in the brain. The major effect of melanocortin in the brain is to reduce food intake however, it has also been shown that melanocortin agonists or antagonists injected directly into the cerebral ventricle affect insulin actions in the periphery while food was withdrawn or while food intake was kept constant (see Schwartz et al, Nature, 2000, 404:661-671; Seeley et al, Ann. Rev. Nutr., 2004, 24:133-149; Cone et al, Recent Prog. Horm. Res., 1996, 51:287-317; Heijbor et al, Diabetologia, 2005, 48:1621-1626; Obici et al, J. Clin. Inv., 2001, 108:1079-1085). Taken together, these data suggest that central administration of melanocortins affects insulin sensitivity and may do so independently of energy balance. Banno et al., (FEBS letters, 2007, 581:1131-1136) demonstrated that intracerebral injections of a melanocortin agonist to DIO rats ameliorated insulin sensitivity in the periphery, decreased the size of and increased the number of adipocytes in white adipose tissue and decreased triglycerides content in the liver.
Considering the large numbers of overweight and/or insulin resistant subjects in need of treatment, intracerebral administration is an unlikely means to disperse medicaments to patients. There is a need in the art, therefore, to identify melanocortin agonists and antagonists suitable for peripheral administration to affect parameters of insulin action and energy metabolism such as insulin sensitivity, cellular characteristics of white adipose tissue, triglyceride levels and the like. Nomenclature and Abbreviations As used herein, an "obese subject" or mammal is characterized as having a body weight approximately 20% or greater than the normal body weight for said subject. Normal body weight may be determined by a comparison of the weight of the subject at a prior point in time, such as when insulin metabolism was normal, or by a comparison of the weight of the subject as compared to averages of other subjects of a similar age and/or condition.
As used herein, an "overweight subject" or mammal is characterized as having a body weight approximately 5% greater to approximately 20% greater than the normal body weight for said subject. Normal body weight may be determined by a comparison of the weight of the subject at a prior point in time, such as when insulin metabolism was normal, or by a comparison of the weight of the subject as compared to averages of other subjects of a similar age and/or condition.
As used herein, a "normal subject" or mammal is characterized as having a body weight up to approximately 5% greater than to approximately 5% less than the normal body weight for said subject. Normal body weight may be determined by a comparison of the weight of the subject at a prior point in time, such as when insulin metabolism was normal, or by a comparison of the weight of the subject as compared to averages of other subjects of a similar age and/or condition.
As used herein, a "lean subject" or mammal is characterized as having a body weight approximately 5% to 30% or even to 50% less than the normal body weight for said subject. Normal body weight may be determined by a comparison of the weight of the subject at a prior point in time, such as when insulin metabolism was normal, or by a comparison of the weight of the subject as compared to averages of other subjects of a similar age and/or condition.
As used herein, the terms "treat", "treating" and "treatment" include palliative, curative and prophylactic treatment. As used herein, "measurable" means the biologic effect is both reproducible and significantly different from the baseline variability of the assay.
As used herein, peripherial administration includes all forms of administration of a compound or a composition comprising a compound of the instant invention which excludes intracranial administration. Examples of peripheral administration include, but are not limited to, oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, implant and the like), nasal, vaginal, rectal, sublingual or topical routes of administration, including transdermal patch applications and the like.
A "subject", as used herein and throughout this application, refers to a mammalian or non-mammalian animal including, for example and without limitation, a human, a rat, a mouse or farm animal. Reference to a subject does not necessarily indicate the presence of a disease or disorder. The term "subject" includes, for example, a mammalian or non-mammalian animal being dosed with a melanocortin analog as part of an experiment, a mammalian or non-mammalian animal being treated to help alleviate a disease or disorder, and a mammalian or non-mammalian animal being treated prophylactically to retard or prevent the onset of a disease or disorder. Subject mammals may be human subjects of any age, such as an infant, a child, an adult or an elderly adult.
A "therapeutically acceptable amount" of a compound or composition of the invention, regardless of the formulation or route of administration, is that amount which elicits a desired biological response in a subject. The biological effect of the therapeutic amount may occur at and be measured at many levels in an organism. For example, the biological effect of the therapeutic amount may occur at and be measured at the cellular level by measuring the response at a receptor which binds melanocortin and/or a melanocortin analog, or the biological effect of the therapeutic amount may occur at and be measured at the system level, such as effecting an increase/decrease in the levels of insulin. The biological effect of the therapeutic amount may occur at and be measured at the organism level, such as the alleviation of a symptom(s) or progression of a disease or condition in a subject. A therapeutically acceptable amount of a compound or composition of the invention, regardless of the formulation or route of administration, may result in one or more biological responses in a subject. In the event that the compound or composition of the invention is subject to testing in an in vitro system, a therapeutically acceptable amount of the compound or composition may be viewed as that amount which gives a measurable response in the in vitro system of choice. The nomenclature used to define the peptides is that typically used in the art wherein the amino group at the N-terminus appears to the left and the carboxyl group at the C-terminus appears to the right. Where the amino acid has D and L isomeric forms, it is the L form of the amino acid that is represented unless otherwise explicitly indicated. The compounds of the invention useful for the treatment of insulin resistance, with or without weight loss, may possess one or more chiral centers and so exist in a number of stereoisomeric forms. All stereoisomers and mixtures thereof are included in the scope of the present invention. Racemic compounds may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilizing methods known to those skilled in the art. In addition, chiral intermediate compounds may be resolved and used to prepare chiral compounds of the invention.
The compounds of the invention useful for the treatment of insulin resistance, with or without weight loss, may exist in one or more tautomeric forms. AU tautomers and mixtures thereof are included in the scope of the present invention. For example, a claim to 2-hydroxypyridinyl would also cover its tautomeric form, α- pyridonyl.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Also, all publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.
Symbol Meaning Abu α-aminobutyric acid
Ac acyl group
Ace l-amino-l-cyclo(C3-C9)alkyl carboxylic acid
A3c 1-amino-l-cyclopropanecarboxylic acid
A4c 1-amino-l-cyclobutanecarboxylic acid A5c l-amino-l-cyclopentanecarboxy lie acid
A6c 1-amino-l-cyclohexanecarboxylic acid
Aha 7-aminoheptanoic acid
Ahx 6-aminohexanoic acid
Aib α-aminoisobutyric acid Aic 2-aminoindan-2-carboxylic acid
Ala or A alanine β-Ala β-alanine
Ape denotes the structure:
Figure imgf000092_0001
Apn 5-aminopentanoic acid (HN-(CH2)4-C(O)
Arg or R arginine hArg homoarginine
Asn or N asparagine
Asp or D aspartic acid BaI 3-benzothienylalanine
Bip 4,4'-biphenylalanine, represented by the structure
Figure imgf000093_0001
— NH- CH — C—
Bpa 4-benzoylphenylalanine
4-Br-Phe 4-bromo-phenylalanine
Cha β-cyclohexylalanine hCha homo-cyclohexylalanine
Chg cyclohexylglycine
Cys or C cysteine hCys homocysteine
Dab 2,4-diaminobutyric acid
Dap 2,3-diaminopropionic acid
Dip ^/?-diphenylalanine
Doc 8-amino-3,6-dioxaoctanoic acid with the structure of:
Figure imgf000093_0002
2-Fua β-(2-furyl)-alanine
Gaba 4-aminobutyric acid
GIn or Q glutamine
GIu or E glutamic acid
GIy or G glycine
His or H histidine
3-Hyp trans-3-hydroxy-L-proline, i.e., (2S, 3S)-3-hy carboxylic acid 4-Hyp 4-hydroxyproline, i.e., (2S, 4R)-4-hydroxypyrrolidine-2-carboxylic acid
He or I isoleucine
Leu or L leucine hLeu homoleucine
Lys or K lysine
Met or M methionine
/-hMet /Miomomethionine
1-Nal /?-(l-naphthyl)alanine:
2-Nal ^?-(2-naphthyl)alanine
Nip nipecotic acid
NIe norleucine
Oic octahydroindole-2-carboxylic acid
Orn ornithine
2-Pal ^?-(2-pyridiyl)alanine
3-Pal /-(3-pyridiyl)alanine
4-Pal ^?-(4-pyridiyl)alanine
Pen penicillamine
Pff (S)-pentafluorophenylalanine
Phe or F phenylalanine hPhe homophenylalanine
Pro or P proline hPro homoproline
Ser or S serine
Tie tert-Leucine
Taz β-(4-thiazolyl)alanine
2-Thi β-(2-thienyl)alanine
3-Thi β-(3-thienyl)alanine
Thr or T threonine
Trp or W tryptophan
Tyr or Y tyrosine D-(Et)Tyr has a structure of
Figure imgf000095_0001
VaI or V valine
Certain other abbreviations used herein are defined as follows:
Boc: fert-butyloxycarbonyl
BzI: benzyl
DCM: dichloromethane
DIC: N, N-diisopropylcarbodiimide
DIEA: diisopropylethyl amine
Dmab: 4-{N-(l-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl) amino} benzyl
DMAP: 4-(dimethylamino)pyridine
DMF dimethylformamide
DNP: 2,4-dinitrophenyl
Fm: fluorenylmethyl
Fmoc: fluorenylmethyloxycarbonyl
For: formyl
HBTU: 2-(lH-benzotriazole-l-yl)-l,l,3/3-tetramethyluronium hexafluorophosphate cHex cyclohexyl
HOAT: O-(7-azabenzotriazol-l-yI)-14,3,3-tetramethyluronium hexafluorophosphate
HOBt: 1 -hy droxy-benzotriazole
MBHA 4-methylbenzhydrylamine
Mmt: 4-methoxytrityl NMP: N-methylpyrrolidone
O-tBu oxy-tert-butyl
Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl
PyBroP bromo-tris-pyrrolidino-phosphonium hexafluorophosphate tBu: tert-butyl
ΗS: triisopropylsilane
TOS: tosyl
Trt trityl
TFA: trifluoro acetic acid TFFH: tetramethylfluoroforamidinium hexafluorophosphate
Z: benzyloxycarbonyl
Unless otherwise indicated, with the exception of the N-terminal amino acid, all abbreviations (e.g. Ala) of amino acids in this disclosure stand for the structure of
-NH-C(R)(R')-CO-, wherein R and R' each is, independently, hydrogen or the side chain of an amino acid (e.g., R = CH3 and R' = H for Ala), or R and R' may be joined to form a ring system.
For the N-terminal amino acid, the abbreviation stands for the structure of:
Figure imgf000096_0001
The designation "NH2" in e.g., Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NHz (SEQ ID NO:7), indicates that the C-terminus of the peptide is amidated. Ac-
Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys) (SEQ ID NO:36), or alternatively Ac-NIe- c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- OH (SEQ ID NO:36), indicates that the C- terminus is the free acid.
"-c(Cys-Cys)-" or "-cyclo(Cys-Cys)-" denotes the structure:
Figure imgf000096_0002
"-c(Cys-Pen)-" or "-cyclo(Cys-Pen)-" denotes the structure:
Figure imgf000097_0001
"-c(Asp-Lys)-" or "-cyclo(Asp-Lys)-" denotes the structure:
Figure imgf000097_0002
Applicants have devised the following shorthand used in naming the specific embodiments and/or species:
"HydantoinC(O)-(Aa-Ab)" denotes the structure:
Figure imgf000097_0003
R7 R6
wherein amino acid "Aa" has the structure:
Figure imgf000097_0004
and
R5 R4
Figure imgf000097_0005
amino acid "Ab" the structure: For example, a compound represented as "c[Hydantoin(C(O)-(Cys-Ab))-A1-A2-A3-A4- Cys]-" would have the following the structure:
Figure imgf000097_0006
whereas a compound represented as "c[Hydantoin(C(O)-(Ab-Cys))-A1-A2-A3-A4- Cys]-" would have the structure:
Figure imgf000098_0001
For further guidance, "c[Hydantoin(C(O)-(Asp-Ab))-A1-A2-A3-A4-Lys]-" represents
the following compound:
Figure imgf000098_0002
, whereas
"c[Hydantoin(C(O)-(Dap-Ab))-A1-A2-A3-A4-Asp]-" has the following formula:
Figure imgf000098_0003
"Acyl" refers to R" -C(O)-, where R" is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, aryl, alkylaryl, or substituted alklyaryl, and is indicated in the general formula of a particular embodiment as "Ac".
"Alkyl" refers to a hydrocarbon group containing one or more carbon atoms, where multiple carbon atoms if present are joined by single bonds. The alkyl hydrocarbon group may be straight-chain or contain one or more branches or cyclic groups.
"Hydroxyalkyl" refers to an alkyl group wherein one or more hydrogen atoms of the hydrocarbon group are substituted with one or more hydroxy radicals, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like.
"Substituted alkyl" refers to an alkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with one or more substituents selected from the group consisting of halogen, (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, and -C1-20 alkyl, wherein said -C1-20 alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, -CF3, -OCH3, -OCF3, and -(CH2)o-2o-COOH. In different embodiments 1, 2, 3 or 4 substituents are present. The presence of -(CH2)o-2o-COOH results in the production of an alkyl acid. Non-limiting examples of alkyl acids containing, or consisting of, -(CH2)o-2o-COOH include 2-norbornane acetic acid, tert-butyric acid, 3-cyclopentyl propionic acid, and the like. The term "halo" encompasses fluoro, chloro, bromo and iodo. "Heteroalkyl" refers to an alkyl wherein one of more of the carbon atoms in the hydrocarbon group is replaced with one or more of the following groups: amino, amido, -O-, -S- or carbonyl. In different embodiments 1 or 2 heteroatoms are present.
"Substituted heteroalkyl" refers to a heteroalkyl wherein one or more hydrogen atoms of the hydrocarbon group are replaced with one or more substituents selected from the group consisting of halogen, (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, -NH2, -NHCH3, -NO2, and -C1-20 alkyl, wherein said -C1-20 alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, -CF3, -OCH3, -OCF3, and -(CH2)o-2o-COOH. In different embodiments 1, 2, 3 or 4 substituents are present. "Alkenyl" refers to a hydrocarbon group made up of two or more carbons where one or more carbon-carbon double bonds are present. The alkenyl hydrocarbon group may be straight-chain or contain one or more branches or cyclic groups.
"Substituted alkenyl" refers to an alkenyl wherein one or more hydrogens are replaced with one or more substituents selected from the group consisting of halogen (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, -NH2, -NHCHs, -NO2, and -Ci-20 alkyl, wherein said -C1-20 alkyl optionally may be substituted with one or more substituents selected, independently for each occurrence, from the group consisting of halogens, -CF3, -OCH3, -OCF3, and -(CH2)(Mo-COOH. In different embodiments 1, 2, 3 or 4 substituents are present. "Aryl" refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to three conjugated or fused ring systems. Aryl includes carbocyclic aryl, heterocyclic aryl and biaryl groups. Preferably, the aryl is a 5- or 6-membered ring. Preferred atoms for a heterocyclic aryl are one or more sulfur, oxygen, and/or nitrogen. Non-limiting examples of aryl include phenyl, 1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, 9-anthracene, and the like. Aryl substituents are selected from the group consisting of -C1-20 alkyl, -C1-20 alkoxy, halogen (i.e., fluorine, chlorine, bromine, and iodine), -OH, -CN, -SH, -NH2, -NO2, -Ci-20 alkyl substituted with halogens, -CF3, -OCF3, and -(CH2)o-2o-COOH. In different embodiments the aryl contains 0, 1, 2, 3, or 4 substituents.
"Alkylaryl" refers to an "alkyl" joined to an "aryl".
The term " (C1-C12)hydrocarbon moiety" encompasses alkyl, alkenyl and alkynyl and in the case of alkenyl and alkynyl there is C2-C12.
For the avoidance of doubt, unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different. For the avoidance of doubt, the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different. The pharmaceutically acceptable salts of the compounds of the invention which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, with carboxylic acids or with organo-sulfonic acids. Examples include the HCl, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts. Compounds of the invention can also provide pharmaceutically acceptable metal salts, in particular non-toxic alkali and alkaline earth metal salts, with bases. Examples include the sodium, potassium, aluminum, calcium, magnesium, zinc and diethanolamine salts (Berge, S. M. et al., ]. Pharm. Sd., 66:1-19 (1977); Gould, P.L., Int'l J. Pharmaceutics, 33:201-17 (1986); and Bighley, L.D. et al, Encyclo. Pharma. Tech., Marcel Dekker Inc, New York, 13:453-97 (1996).
The pharmaceutically acceptable solvates of the compounds of the invention include the hydrates thereof. Also included within the scope of the invention and various salts of the invention are polymorphs thereof. Hereinafter, compounds their pharmaceutically acceptable salts, their solvates or polymorphs, defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention". In vitro studies
Compounds of the present invention can be and were tested for activity as ligands of one or more of the melanocortin receptors according to the following procedures. One skilled in the art would know that procedures similar to those described herein may be used to assay the binding activities of the compounds of the invention to melanocortin receptor molecules. Radioligand Binding Assays Cellular membranes used for the in vitro receptor binding assays were obtained from transgenic CHO-Kl cells stably expressing hMC-R receptor subtypes 1, 3, 4 or 5. The CHO-Kl cells expressing the desired hMC-R receptor type were sonicated (Branson® setting 7, approximately 30 sec) in ice-cold 50 mM Tris-HCl at pH 7.4 and then centrϋuged at 39,000 g for 10 minutes at approximately 4°C. The pellets were resuspended in the same buffer and centrifuged at 50,000 g for 10 minutes at approximately 4°C. The washed pellets containing the cellular membranes were stored at approximately - 800C.
Competitive inhibition of [125I](Tyr2)-(Nle4-D-Phe7)α-MSH ([125I]-NDP-Ct-MSH, Amersham Biosciences®) binding was carried out in polypropylene 96 well plates. Cell membranes (1-10 μg protein/well) prepared as described above were incubated in 50 mM Tris-HCl at pH 7.4 containing 0.2% bovine serum albumin (BSA), 5 mM MgCh, 1 mM CaCh and 0.1 mg/mL bacitracin, with increasing concentrations of the test compound and 0.1-0.3 nM [125I]-NDP-α-MSH for approximately 90-120 minutes at approximately 37°C. Bound [125I]-NDP-α-MSH ligand was separated from free [125I]- NDP-α-MSH by filtration through GF/C glass fiber filter plates (Unifilter®; Packard) presoaked with 0.1 % (w/v) polyethylenimine (PEI), using a Packard Filtermate® harvester. Filters were washed three times with 50 mM Tris-HCl at pH 7.4 at a temperature of approximately 0-40C and then assayed for radioactivity using a Packard Topcount® scintillation counter. Binding data were analyzed by computer- assisted non-linear regression analysis (XL fit; IDBS). A selection of the preferred embodiments was tested using the above-discussed assay and the binding constants (Ki in nM) are reported in Tables 5, 6, 7 and 8.
TABLE 5 - Radioligand Binding Assay Data for Selected Compounds Table 5A
Figure imgf000102_0001
Table 5B
Figure imgf000102_0002
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
TABLE 7 - Binding Constants for Formula (V) Examples Table 7A
Figure imgf000113_0002
TABLE 7B - Bindine Constants for Formula (VTI Ex<
Figure imgf000114_0001
Figure imgf000115_0001
TABLE 7C - Binding Constants for Formula (VII) Examples
Figure imgf000115_0002
Figure imgf000115_0003
Figure imgf000116_0001
Melanocortin Functional Activity and Selectivity
The compounds of the present invention will interact preferentially (i.e., selectively) to MC-4 relative to the other melanocortin receptors. Selectivity is particularly important when the compounds are administered to humans or other animals to minimize the number of side effects associated with their administration.
MC-4 selectivity of a compound is defined herein as the ratio of the ECso of the compound for an MC-I receptor (ECso -MC-I) over the ECso of the compound for the
MC-3 (ECso -MC-3)/MC-4 (ECso -MC-4) receptor, the ECso values being measured as described above. The formulas are as follows:
MC-3 selectivity = [ECso-MC-lMECso-MCS] MC-4 selectivity = [ECao-MC-l]/[ECso-MC-4]
A compound is defined herein as being "selective for the MC-3 receptor" when the above mentioned ratio "MC-3-selectivity" is at least about 10, preferably at least about 100, and more preferably at least about 500.
A compound is defined herein as being "selective for the MC-4 receptor" when the above mentioned ratio "MC-4-selectivity" is at least about 10, preferably at least about 100, and more preferably at least about 500.
One skilled in the art would know that procedures similar to those described herein may be used to assay the binding activities of the compounds of the invention to melanocortin receptor molecules. cyclic AMP Bioassay
Intracellular cyclic AMP (cAMP) levels were determined by an electrochemiluminescence (ECL) assay (Meso Scale Discovery ®, Gaithersburg, MD; referred to hereinafter as MSD). CHO-Kl cells stably expressing the hMC receptor subtypes were suspended in RMPI 1640® assay buffer (RMPI 1640 buffer contains 0.5 mM isobutylmethylxanthine (IBMX), and 0.2% protein cocktail (MSD blocker A)). Transgenic CHO-Kl cells stably expressing hMC receptor subtypes 1, 3, 4 or 5 were dispensed at a density of approximately 7,000 cells/well in 384-well Multi-Array® plates (MSD) containing integrated carbon electrodes and coated with anti-cAMP antibody. Increasing concentrations of the test compounds were added and the cells were incubated for approximately 40 minutes at approximately 37°C. Following this incubation, lysis buffer (HEPES-buffered saline solution with MgCh and Triton X- 100® at ph 7.3) containing 0.2% protein cocktail and 2.5 nM TAG™ ruthenium- labeled cAMP (MSD) was added and the cells were incubated for approximately 90 minutes at room temperature. At the end of the second incubation period read buffer (Tris-buffered solution containing an ECL co-reactant and Triton X-100 at ph 7.8) was added and the cAMP levels in the cell lysates were immediately determined by ECL detection with a Sector Imager 6000 reader® (MSD). Data were analyzed using a computer-assisted non-linear regression analysis (XL fit; IDBS) and reported as either an ECso value or a Kb value. ECso represents the concentration of an agonist compound needed to obtain
50% of the maximum reaction response, e.g., 50% of the maximum level of cAMP as determined using the assay described above. The Kb value reflects the potency of an antagonist and is determined by Schild analysis. In brief, concentration-response curves of an agonist are carried out in the presence of increasing concentrations of an antagonist. The Kb value is the concentration of antagonist which would produce a 2-fold shift in the concentration-response curve for an agonist. It is calculated by extrapolating the line on a Schild plot to zero on the y-axis.
A selection of compounds was tested using the above-discussed assays and the results are reported in Tables 9, 10, 11, and 12. TABLE 9 - cAMP Bioassay Data for Selected Compounds Table 9A
Figure imgf000117_0001
Figure imgf000118_0002
Figure imgf000118_0001
Figure imgf000119_0001
ND = not determined Table 9C
Figure imgf000119_0002
Figure imgf000120_0001
Table 9D
Figure imgf000120_0002
Table IQA
Figure imgf000120_0003
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
TABLE 11 - Intracellular Cyclic AMP (cAMP) Levels for Formula (I) Examples Table HA
Figure imgf000127_0002
TABLE HB -
Figure imgf000127_0003
Figure imgf000128_0001
Figure imgf000129_0001
TABLE HC
Figure imgf000129_0002
TABLE 12-cAMP Bioassay Data for Selected Compounds
Figure imgf000129_0003
In vivo studies
Compounds of the present invention can be and were tested for an effect upon insulin resistance and/or body weight according to the following procedures. One skilled in the art would know that procedures similar to those described herein may be used to assay the effect of the compounds of the invention upon insulin resistance and/or body weight.
Ligand compounds activating melanocortin receptors tested in the in vivo studies were as follows (Table 13): Table 13
Figure imgf000130_0001
Acute feeding experiments (fasting)
Male Sprague Dawley rats (25Og) were housed in individual cages and maintained under 12:12 hour light:dark conditions. The rats were fasted for 18 hours prior to the start of the experiment with water available ad libitum. At time 0, the rats were injected subcutaneously (sc) with selected compounds at doses of 100 nmole/kg, or with vehicle, and were provided with food. Individual food consumption was measured at about 2, 4 and 6 hours after injection. Data for selected compounds of the invention are reported in Figure 1. Chronic feeding experiments Male, Sprague Dawley rats that had been fed either a normal diet (30Og;
Research Diets 12450) or a high fat diet (40Og; Research Diets 12451) for 10 weeks prior to the start of the experiment were housed in individual cages and maintained under 12:12 hour light:dark conditions with both food and water available ad libitum. The rats were anesthetized and implanted subcutaneously with an osmotic mini pump (Alzet, Cupertino, CA). The pumps delivered either Compound A or Compound B at doses of 75, 300 or 1200 nmole/kg/day, or vehicle for 7 days. Individual body weight and food consumption were measured daily.
On day 7 rats were anesthetized and fit with a jugular-right atrial cannula. On day 8 an iv glucose tolerance test was performed and blood samples were withdrawn into heparinized syringes at time -10 and 0. Immediately after the time 0 blood sample, the rats were injected with glucose (lg/kg) via the indwelling cannula. Subsequent blood samples were withdrawn at 2.5, 5, 10, 20 and 40 minutes later. Plasma levels of glucose (Diagnostic Chemicals Limited) and insulin (Alpco) were determined by commercially available kits. Results are showin in Figures 2A-D and 3A-D.
Glucose tolerance tests
Male, C57BL/6 mice that had been fed either a normal diet (3Og; Research Diets 12450) or a high fat diet (45g; Research Diets 12452) for 12 weeks prior to the start of the experiment were housed in individual cages and maintained under 12:12 hour light:dark conditions with both food and water available ad libitum. The mice were anesthetized and implanted subcutaneously with an osmotic mini pump (Alzet, Cupertino, CA). The pumps delivered Compound A at doses of 200, 600 or 1800 nmole/kg/day, or vehicle for 14 days. On day 14 the mice were fasted for 18 hours or overnight. On day 15 an glucose tolerance test was performed by injecting the mice with glucose (2g/kg) ip. Blood samples were taken by tail stick at 0, 15, 30, 60 and 180 minutes after the glucose injection and blood glucose level was measured using an Accu-Chek glucometer. Results are shown in Figure 4.
Male, Lepob/Lepob mice (5Og) were group housed maintained under 12:12 hour light:dark conditions with both food and water available ad libitum. The mice were fasted for 18 hours or overnight and an ip glucose tolerance test was performed. Mice were injected with Compound A ip at a dose of 6.4μmole/kg at -15 minutes and a blood sample was taken by tail stick. At time 0 mice were injected ip with glucose (lg/kg) and blood samples were taken by tail stick at 0, 15, 30, 60 and 90 minutes later and blood glucose level was measured using Glucometer Elite XL (Bayer Corporation). Results are shown in Figure 5.
Administration and Use
The peptides of this invention can be provided in the form of pharmaceutically acceptable salts. Examples of such salts include, but are not limited to, those formed with organic acids (e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluenesulfonic, or pamoic acid), inorganic acids (e.g., hydrochloric acid, sulfuric acid, or phosphoric acid), and polymeric acids (e.g., tannic acid, carboxymethyl cellulose, polylactic, polyglycolic, or copolymers of polylactic-glycolic acids). A typical method of making a salt of a peptide of the present invention is well known in the art and can be accomplished by standard methods of salt exchange. Accordingly, the TFA salt of a peptide of the present invention (the TFA salt results from the purification of the peptide by using preparative HPLC, eluting with TFA containing buffer solutions) can be converted into another salt, such as an acetate salt, by dissolving the peptide in a small amount of 0.25 N acetic acid aqueous solution. The resulting solution is applied to a semi- prep HPLC column (Zorbax®, 300 SB, C-8). The column is eluted with: (1) 0.1N ammonium acetate aqueous solution for 0.5 hours; (2) 0.25N acetic acid aqueous solution for 0.5 hours; and (3) a linear gradient (20% to 100% of solution B over 30 minutes) at a flow rate of 4 ml/min (solution A is 0.25N acetic acid aqueous solution; solution B is 0.25N acetic acid in acetonitrile/water, 80:20). The fractions containing the peptide are collected and lyophilized to dryness. As is well known to those skilled in the art, the known and potential uses of peptides with melanocortin receptor (MC-R) agonist or antagonist activity is varied and multitudinous, thus the administration of the compounds of this invention for purposes of eliciting an agonist effect can have the same effects and uses as melanocortin itself. Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of formula (I) in association with a pharmaceutically acceptable carrier.
The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. In general, an effective dosage for the activities of this invention is in the range of lxlO"7 to 200 mg/kg/day, preferably lxlfr4 to 100 mg/kg/day which can be administered as a single dose or divided into multiple doses. The compounds of this invention can be administered by oral, parenteral
(e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Preparations may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. Preparations can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.
Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
Further, a compound of this invention can be administered in a sustained release composition such as those described in the following patents and patent applications. U.S. Patent No. 5,672,659 teaches sustained release compositions comprising a bioactive agent and a polyester. U.S. Patent No. 5,595,760 teaches sustained release compositions comprising a bioactive agent in a gelable form. U.S. Patent No. 5,821,221 teaches polymeric sustained release compositions comprising a bioactive agent and chitosan. U.S. Patent No. 5,916,883 teaches sustained release compositions comprising a bioactive agent and cyclodextrin. The teachings of the foregoing patents and applications are incorporated herein by reference.

Claims

What is claimed is:
1. A method of treating insulin resistance in a subject in need thereof, comprising peripheral administration of an effective amount of a melanocortin receptor 4 agonist to treat said insulin resistance in said subject in need thereof.
2. The method according to claim 1, where in said melanocortin receptor 4 agonist useful to treat insulin resistance is selected from the group consisting of: Ac-Nle-c(Asp-His-D-Phe-Arg-Trp/?- Ala-Lys)-NH2; SEQ ID NO:1 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH2; SEQ ID NO:1 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp- Ahx-Cys)-NH2; SEQ ID NO:2 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH2; SEQ ID NO:3 D-Phe-c(Cys-His-D-Phe-Arg-Trp-^-Ala-D-Cys)-Thr-NH2; SEQ ID NO:3 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH2; SEQ ID NO:3 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:2 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH2; SEQ ID NO:4 Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:5 Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6 Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:6 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 Ac-Nle-c(Cys-/-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 Ac-Nle-c(Cys- Aib-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:7 Ac-Nle-cφ-Cys-AIa-His-D-Phe-Arg-Trp-CysJ-Nrt; SEQ ID NO:8 Ac-Nle-c(D-Cys-D- Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8 Ac-Nle-c(D-Cys-/- Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8 Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8 Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:8 Ac-NIe-C(D-CyS-GIy-HiS-D-PhC-Ar8-TrP-CyS)-NH2; SEQ ID NO:8 Ac-Nle-c(Cys-D-A la-His-D-Phe-Arg-Trp-D-Cy S)-NH2; SEQ ID NO:9 Ac-Nle-c(Cys-/-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9 Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9 Ac-Nle-c(Cys- Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9 Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:9 Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10 Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10 Ac-Nle-c(D-Cys:/J-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10 Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10 Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH2; SEQ ID NO:10 Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11 Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11 Ac-Nip-c( Asp-His-D-Phe- Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11 Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11 Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11 Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO: 11 Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 n-butanoyl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:12 Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-j?-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:11 Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13 Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13 Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2,- SEQ ID NO:13 Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp- AIa-LyS)-NH2; SEQ ID NO:13 Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2; SEQ ID NO:13 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH2; SEQ ID NO: 14 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-j?- AIa-LyS)-NH2; SEQ ID NO:14 Ac-Nle-cCAsp-His-D-Phe-Arg-D-Trp-Gaba-LysJ-NPfc; SEQ ID NO: 14 Ac-Nle-cCAsp-His-D-Phe-Arg-D-Trp-Aha-LysJ-NI-fc; SEQ ID NO:14 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH2; SEQ ID NO: 14 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH2; SEQ ID NO:15 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH2; SEQ ID NO:15 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp- Ahx-Cys)-NH2; SEQ ID NO:15 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-/?-Ala-Cys)-NH2; SEQ ID NO:15 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH2; SEQ ID NO:15 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:16 Ac-Nle-c(Cys-D- Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH>; SEQ ID NO:16 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-l-Nal-Cys)-NH2; SEQ ID NO:16 n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO: 17 n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:17 Ac-Nle-c(Cys-D- Ala-His-D-Phe-Arg-2-Nal-Cys)-NH2; SEQ ID NO:18 Ac-Nle-c(Cys-D- Ala-His-D-Phe-Arg-1-Nal-Cys)-NH2; SEQ ID NO:18 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH2; SEQ ID NO:18 Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:59 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH2; SEQ ID NO:19 Ac-Nle-c(Cys-D- Ala-His-D-2-Nal-Arg-Bal-Cys)-NH2; SEQ ID NO:20 Ac-NIe-C(Pen-D-AIa-HiS-D-PlIe-Ar8-TrP-CyS)-NH2; SEQ ID NO:21 Ac-Nle-c(Cys-D- Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:22 D-Phe-c(Cys-His-D-Phe-hArg-Trp:/?-Ala-D-Cys)-Thr-NH2; SEQ ID NO:23 D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-j?-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24 D-Phe-c(Cys-His-D-Phe-Arg-Bip:/?-Ala-D-Cys)-Thr-NH2; SEQ ID NO:25
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr-NH2; SEQ ID NO:24 D-Phe-c(Cys-His-D-Phe-hArg-Bip-^-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26 D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-/?-Ala-D-Cys)-Thr-NH2; SEQ ID NO:26 Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:27 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH2; SEQ ID NO:28 Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH2; SEQ ID NO:28 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; SEQ ID NO:29 Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Cys-D- Val-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH-; SEQ ID NO:30 Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:30 Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:31 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32 Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:32 Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:33 Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34 Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:34 Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:35 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:36 Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH2; SEQ ID NO:37 Ac-Nle-cCAsp-His-D^-Nal- Arg-Trp-Ala-Lys)-NH2; SEQ ID NO:38 Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-/?- AIa-LyS)-NH2; SEQ ID NO:38 Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:39 Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH2; SEQ ID NO:39 Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40 Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH2; SEQ ID NO:40 Ac-Nle-c(Asp-His-D-Phe-Arg-TrP:/?-Ala-Lys)-OH; SEQ ID NO:41 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH; SEQ ID NO:42 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH; SEQ ID NO:43 D-Phe-c(Cys-His-D-Phe-Arg-Trp-/?-Ala-D-Cys)-Thr-OH; SEQ ID NO:43 D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH; SEQ ID NO:43 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH; SEQ ID NO:42 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH; SEQ ID NO:41 Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; SEQ ID NO:44 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH; SEQ ID NO:45 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp- Ahx-Cys)-OH; SEQ ID NO:45 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-j?- Ala-Cys)-OH; SEQ ID NO:45 Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D- Ala-Cys)-OH; SEQ ID NO:45 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH; SEQ ID NO:46 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH; SEQ ID NO:46 Ac-Nle-c(Cys-D- Ala-His-D-2-Nal-Arg-l-Nal-Cys)-OH; SEQ ID NO:46 Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH; SEQ ID NO:46 Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; SEQ ID NO:47 Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH; SEQ ID NO:48
Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; SEQ ID NO:49 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:50 Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; SEQ ID NO:50 Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:51 Ac-D- Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:52 Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH2; SEQ ID NO:52 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; SEQ ID NO:51 Ac-D- Arg-c(Asp-His-D-Phe-Arg-Trp- AIa-LyS)-NH2; SEQ ID NO:53 Ac-Arg-cCAsp-His-D-Phe-Arg-Trp- Ala-Lys)-NH2; SEQ ID NO:53 Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:35
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH2; SEQ ID NO:54 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH2; SEQ ID NO:54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-/?-Ala-Cys)-NH2; SEQ ID NO:54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH2; SEQ ID NO:54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH2; SEQ ID NO:54 Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:55
Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH2; SEQ ID NO:55
Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:56
Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal- AIa-CyS)-NH2; SEQ ID NO:56
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH2; SEQ ID NO:57 Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH2; SEQ ID NO:57
Ac-Nle-cCAsp-D-Ala-His-D-Phe-Arg-Bal-Ala-LysJ-NH∑; SEQ ID NO:58
Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-NH2;
(SEQ ID NO:60)
Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-Doc-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)- NH2; (SEQ ID NO:61)
Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-^-Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-
NH2; (SEQ ID NO:62)
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)->Ala-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-
(Arg)3-NH2; (SEQ ID NO:62) Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-(Arg)3-
NH2; (SEQ ID NO:63)
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Pro)2-Lys-Asp-Tyr-Gly-Arg-(Lys)2-(Arg)2-
Gln-(Arg)3-NH2; (SEQ ID NO:64)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Gly-Cys)-(Pro)2-Lys-Asp-Tyr-Gly-Arg-(Lys)2- (Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:65)
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(/?-Ala)2-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-
(Arg)3-NH2; (SEQ ID NO:66)
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Pro)2-Lys-Asp-Doc-Tyr-Gly-Arg-(Lys)2-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:67) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Gly-Cys)-(Pro)2-Lys-Asp-Doc-Tyr-Gly-Arg-
(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:68) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-
(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:69)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-Doc-Tyr-Gly-Arg-
(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:69) Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-
(Arg)3-NH2; (SEQ ID NO:70)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Tyr-Gly-Arg-
(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:71)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-(Arg)5-Gln- (Arg)3-NH2; (SEQ ID NO:72)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Gly-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:73)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-(Arg)5-
GIn-(AFg)3-NH2; (SEQ ID NO:74) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-
(Lys)2-Arg-Gln-(Arg)4-NH2; (SEQ ID NO:75)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-
(Lys)2-Gln-(Arg)5-NH2; (SEQ ID NO:76)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-Arg- Lys-Gtn-Lys-(Arg)5-NH2; (SEQ ID NO:77)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Tyr-Gly-Arg-
(Lys)2-(Arg)4-Gln- Arg-NH2; (SEQ ID NO:78)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Aib-Arg-
(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:79) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-(Arg)5-Gln-
(AFg)3-NH2; (SEQ ID NO:80)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-(Arg)5-Gln-
(AFg)3-NH2; (SEQ ID NO:80)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-(Arg)6-Gln- (AFg)3-NH2; (SEQ ID NO:81) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-JJ-Ala-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:82)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp->Ala-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:82) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-(Arg)6-Gln-
(Arg)3-NH2; (SEQ ID NO:81)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-j8-Ala-(Arg)6-Gln-
(Arg)3-NH2; (SEQ ID NO:83)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-/-Ala-(Arg)5-Gln- (Arg)3-NH2; (SEQ ID NO:84)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-(Arg)6-Gln-
(Arg)3-NH2; (SEQ ID NO:83)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-Arg-
(Lys)2-(Arg)3-Gln-(Arg)2-NH2; (SEQ ID NO:85) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Tyr-Gly-Arg-
Gln-(Lys)2-(Arg)5-NH2; (SEQ ID NO:86)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-Arg-
(Lys)2-(Arg)5-Gln-NH2; (SEQ ID NO:87)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-Arg- (Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:71)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp->Ala-Tyr-Gly-Arg-
(Lys)2-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:71)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-(Arg)2-Lys-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:88) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Arg-Lys-
(Arg)3-Gln-( AFg)3-NH2; (SEQ ID NO:89)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-(Arg)2-Lys-
(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:88)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)2- Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:90) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/?-Ala-Gly-(Arg)2-Lys-
(Arg)2-Glr>-(Arg)3-NH2; (SEQ ID NO:91)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp->Ala-Gly-Arg-Lys-
(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:92) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)2-
Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:95)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-
Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:96)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Gly-(Arg)2-Lys- (Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:97)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Gly-Arg-Lys-
(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:92)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/?-AIa-(Arg)2-Lys-
(Arg)2-Glri-(Arg)3-NH2; (SEQ ID NO:98) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Arg-Lys-
(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:99)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Tyr-Gly-Arg-
Lys-(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO: 101)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^Ala-(Arg)2-Lys- (Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:104)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Arg-Lys-(Arg)3-
GIn-(AFg)3-NH2; (SEQ ID NO:105)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)2-
Lys-(Arg)2-Gln-(Arg)3-NH2; (SEQ ID NO:100) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-Tyr-Gly-Arg-Lys-
(Arg)3-Gln-(Arg)3-NH2; (SEQ ID NO:101)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys- Asp-^-Ala-Gly^Arg^-Lys-
(Arg)2-Gln-( AFg)3-NH2; (SEQ ID NO:102)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Gly-Arg-Lys- (AFg)3-GIn-(AFg)3-NH2; (SEQ ID NO: 103) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:113)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp-_/?-Ala-(Arg)s-Gln-
(Arg)3-NH2; (SEQ ID NO:113) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-_^-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)3-NH2; (SEQ ID NO:114)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp-j3-Ala-Tyr-Gly-(Arg)5-
GIn-(AFg)3-NH2; (SEQ ID NO:114)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-(Arg)5-Gln- (Arg)4-NH2; (SEQ ID NO:115)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp-/-Ala-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:115)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)4-NH2; (SEQ ID NO:116) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Arg-Asp->Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)4-NH2; (SEQ ID NO:116)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:118)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp-^-Ala-(Arg)5-Gln- (Arg)4-NH2; (SEQ ID NO:118)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp-^-Ala-(Arg)6-Gln-
(AFg)3-NH2; (SEQ ID NO:119)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)3-NH2; (SEQ ID NO:120) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp->Ala-Tyr-Gly-
(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:120)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)4-NH2; (SEQ ID NO:121)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp-^-Ala-Tyr-Gly- (Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:121) Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)6-
Gln-(Arg)3-NH2; (SEQ ID NO:122)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Arg-Asp-/?-Ala-Tyr-Gly-
(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO:122) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-^-Ala-(Arg)6-Gln-
(Arg)3-NH2; (SEQ ID NO:124)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-/?-Ala-(Arg)5-Gln-
(AFg)4-NH2; (SEQ ID NO:125)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2- Arg-Asp-/?-Ala-(Arg)5-Gln- (Arg)4-NH2; (SEQ ID NO:125)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-^Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)3-NH2; (SEQ ID NO:126)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-/?-Ala-Tyr-Gly-
(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:126) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp->Ala-Tyr-Gly-(Arg)6-
Gln-(Arg)3-NH2; (SEQ ID NO:127)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-/?-Ala-Tyr-Gly-
(Arg)6-Gln-(Arg)3-NH2; (SEQ ID NO:127)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp->Ala-Tyr-Gly-(Arg)5- GIn-(AFg)4-NH2; (SEQ ID NO:128)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Arg-Asp-j?-Ala-Tyr-Gly-
(Arg)5-Glrv-(Arg)4-NH2; (SEQ ID NO:128)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp:/?-Ala-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:130) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-/?-Ala-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:130)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-^-Ala-Tyr-Gly-(Arg)5-
Gln-(Arg)3-NH2; (SEQ ID NO:133)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-^-Ala-Tyr-Gly-(Arg)5- Gln-(Arg)4-NH2; (SEQ ID NO:134) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp:/?-Ala-Tyr-Gly-(Arg)5-
GIn-(AFg)4-NH2; (SEQ ID NO:134)
Ac-c(Cys-Glu-His-D-2-NaI-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-/-Ala-Tyr-Gly-(Arg)6-
Gln-(Arg)3-NH2; (SEQ ID NO:135) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Arg-Asp-^-Ala-Tyr-Gly-(Arg)6-
Gln-(Arg)3-NH2; (SEQ ID NO:135)
Ac-NIe-C(CyS-D-AIa-HiS-D-PlIe- Arg-Trp-Cys)-(Doc)2-Tyr-Gly-Arg-(Lys)2-(Arg)2-Gln-
(Arg)3-NH2; (SEQ ID NO:136)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys):/?-Ala-Tyr-Gly-Arg-(Lys)2-Arg-Gln- (AFg)4-NH2; (SEQ ID NO:137)
Ac-NIe-C(CyS-D-AIa-HiS-D-PHe-AFg-TrP-CyS)-DoC-TyF-GIy-AFg-(LyS)2-(AFg)2-GIn-
(AFg)3-NH2; (SEQ ID NO:136)
Ac-NIe-C(CyS-D-AIa-HiS-D-PHe-AFg-TFp-CyS)-Z-AIa-(AFg)S-GIn-(AFg)3-NH2; (SEQ ID
NO:138) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)->Ala-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:138)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Z-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:139)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-/?-Ala-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:140)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-/-Ala-Tyr-Gly-(Arg)2-Lys-(Arg)2-Gln-
(AFg)3-NH2; (SEQ ID NO:141)
Ac-NIe-C(CyS-D-AIa-HiS-D-PHe-AFg-TFp-CyS)-Z-AIa-TyF-GIy-AFg-LyS-(AFg)3-GIn-
(AFg)3-NH2; (SEQ ID NO:142) Ac-NIe-C(CyS-D-AIa-HiS-D-PHe-AFg-TFp-CyS)-Z-AIa-GIy-(AFg)2-LyS-(AFg)2-GIn-
(AFg)3-NH2; (SEQ ID NO:141)
Ac-NIe-C(CyS-D-AIa-HiS-D-PHe-AFg-TFp-CyS)-Z-AIa-GIy-AFg-LyS-(AFg)3-GIn-(AFg)3-
NH2; (SEQ ID NO:142)
Ac-NIe-C(CyS-D-AIa-HiS-D-PHe-AFg-TFp-CyS)-Z-AIa-(AFg)2-LyS-(AFg)2-GIn-(AFg)S- NH2; (SEQ ID NO:143) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-j?-Ala-Arg-Lys-(Arg)3-Gln-(Arg)3-NH2;
(SEQ ID NO:144)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:148) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:148)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:149);
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3- NH2;.(SEQ ID NO:149)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:151)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:150) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:150)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:151)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:152)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:152)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys):/?-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO: 154) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)->Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:153)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:154)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:155) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:155)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:157) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:156)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:156)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:157)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:158)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:158) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:159)
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys):/?-Ala-(Arg)5-Glii-(Arg)3-NH2; (SEQ ID
NO:160)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:161)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO: 162)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:164) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys):/?-Ala-Gly-(Arg)5-Glii-(Arg)3-NH2; (SEQ ID
NO:163)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:163)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:164) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(/?-Ala)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:165)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(/?-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:165) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:166)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:166)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:168)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:167)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:167) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:168)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)->Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:170)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys):/?-Ala-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:169)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-^-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:169)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO: 170) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(/?-Ala)2-GIy-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:171)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:171)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Tyr-Gly-(Arg)s-Gln-(Arg)4-NH2; (SEQ ID NO:173) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:172)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:172) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:173)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:174)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Lys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:174)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-^-Ala-Lys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:175)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-/-Ala-Lys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO: 176) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-j?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:177)
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:178)
D-Phe-c(Cys-His-D-Phe-Arg-Trp-^-Ala-D-Cys)-Thr:/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3- NH2; (SEQ ID NO:179)
D-Phe-c(Cys-His-D-Phe-Arg-Trp-^-Ala-D-Cys)-Thr-^-Ala-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:180)
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:181) Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:182)
Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:183)
Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:184) Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:183)
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO: 185) Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:186)
Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:185)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3- NH2; (SEQ ID NO:186)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:188)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:187) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(/?-Ala)2-(Arg)5-Gln-( AFg)3-NH2; (SEQ
ID NO:188)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:189)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO: 190)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:189)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO: 190) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:191)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys):/?-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:192)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4- NH2; (SEQ ID NO:191) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:192)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:193) Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:194)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-Tyr-Gly-(Arg)s-Gln-(Arg)4-
NH2; (SEQ ID NO:193)
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:194)
Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:195)
Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:196) Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:197)
Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:198)
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3- NH2;.(SEQ ID NO:199)
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:200)
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-j?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:199) Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-^-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:200)
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-/?-Ala-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:201)
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Tφ:/?-Ala-Cys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:202) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:203)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen):/?-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:203) Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-^-Ala-(Arg)s-Gln-(Arg)3-NH2; (SEQ ID
NO:205)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
Figure imgf000154_0001
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(/?-Ala)2-Gly-(Arg)5-Glri-(Arg)3-NH2; (SEQ ID NO:204)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(/?-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:205)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:207) Ac-Nle-c(Cys-D- Ala-His-D-Phe-Arg-Trp-Pen)-Doc-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:206)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:206)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:207)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(Doc)2-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:208)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:208) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:209)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-^-Ala-D-Cys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:210)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys):/?-Ala-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:209) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-/?-Ala-D-Cys)-^-Ala-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:211)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-^-Ala-D-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-
(AFg)3-NH2; (SEQ ID NO:212) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-/?-Ala-D-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:213)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp->Ala-D-Cys)-(/?-Ala)2-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:213)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-TrP:/?-Ala-D-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:267)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-/-Ala-D-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:214)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:216) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-^-Ala-D-Cys)-Doc-Gly-(Arg)5-Glii-(Arg)3-NH2;
(SEQ ID NO:214)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-^-Ala-D-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:217)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3- NH2; (SEQ ID NO:215)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys)-(Doc)2-(Arg)5-Glii-(Arg)3-NH2;
(SEQ ID NO:216)
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys)-(Doc)2-Gly-(Arg)5-Glri-(Arg)3-
NH2; (SEQ ID NO:215) D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp:/?-Ala-D-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:217)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-^-Ala-D-Cys)-Thr:/?-Ala-Tyr-Gly-(Arg)5-Gln-
(AFg)3-NH2; (SEQ ID NO:218)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Tφ-J?-Ala-D-Cys)-Thr-/-Ala-(Arg)5-Gln-(Arg)3- NH2; (SEQ ID NO:219) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-/?-Ala-D-Cys)-Thr-(/?-Ala)2-Tyr-Gly-(Arg)s-Gln-
(Arg)3-NH2; (SEQ ID NO:218)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-/?-Ala-D-Cys)-Thr-(^-Ala)2-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:219) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-j?-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:221)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-^-Ala-D-Cys)-Thr-Doc-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:220)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-/-Ala-D-Cys)-Thr-(Doc)2-Tyr-Gly-(Arg)s-Gln- (Arg)3-NH2; (SEQ ID NO:221)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-^-Ala-D-Cys)-Thr-^-Ala-Tyr-Gly-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:222)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-^-Ala-D-Cys)-Thr-^-Ala-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:223) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr-(/?-Ala)2-Tyr-Gly-(Arg)5-Glii-
(Arg)4-NH2; (SEQ ID NO:222)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr-(^-Ala)2-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:223)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp:/?-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln- (AFg)4-NH2; (SEQ ID NO:224)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-/?-Ala-D-Cys)-Thr-Doc-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:225)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-^-Ala-D-Cys)-Thr-(Doc)2-Tyr-Gly-(Arg)5-Gln-
(Arg)4-NH2; (SEQ ID NO:224) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-^-Ala-D-Cys)-Thr-(Doc)2-(Arg)5-Gln-(Arg)4-
NH2L(SEQ ID NO:225)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip:/?-Ala-D-Cys)-Thr:/?-Ala-Tyr-Gly-(Arg)5-Gln-
(AFg)3-NH2; (SEQ ID NO:227)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-/-Ala-D-Cys)-Thr-/-Ala-Tyr-Gly-(Arg)5-Gln- (Arg)4-NH2; (SEQ ID NO:226) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip:/?-Ala-D-Cys)-Thr:/?-Ala-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:228)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-/?-Ala-D-Cys)-Thr-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:227) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-/-Ala-D-Cys)-Thr-(^-Ala)2-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:228)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-/-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln-
(ATg)3-NH2; (SEQ ID NO:229)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-/-Ala-D-Cys)-Thr-Doc-Tyr-Gly-(Arg)5-Gln- (Arg)4-NH2; (SEQ ID NO:230)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-^-Ala-D-Cys)-Thr-Doc-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:232)
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip:/?-Ala-D-Cys)-Thr-(Doc)2-Tyr-Gly-(Arg)5-Gln-
(Arg)3-NH2; (SEQ ID NO:231) D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-/-Ala-D-Cys)-Thr-(Doc)2-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:232)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:233)
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:234)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-j?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:235)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys):/?-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:236) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:235)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:236)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:237) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-^-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:238)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:237) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:238)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-Tyr-Gly-(Arg)s-Gln-(Arg)3-NH2; (SEQ
ID NO:239)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:240)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:239)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:240) Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:241)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2, (SEQ ID
NO:242)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:241)
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:242)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)->Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:243) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)->Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:244)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:243)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:244) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:245)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:246) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2;.(SEQ ID NO:245)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:246)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:247)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-^-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:248)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:247) Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:248)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:249)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:250)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:249)
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:250) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-^-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:251)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:252)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3- NH2; (SEQ ID NO:251) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(^-Ala)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:252)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:253) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Ghv(Arg)3-NH2; (SEQ ID
NO:254)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-
NH2; (SEQ ID NO:253)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:254)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:255)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys):/?-Ala-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:256) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:255)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:256)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:257)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:258)
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-
NH2; (SEQ ID NO:257) Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:258)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-/-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:259)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-/-Ala-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:260) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2;
(SEQ ID NO:259)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)3-NH2, (SEQ ID
NO:260) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys):/?-Ala-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2;
(SEQ ID NO:261)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-^-Ala-(Arg)s-Gln-(Arg)4-NH2; (SEQ ID
NO:262)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(^-Ala)2-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID NO:261)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(/?-Ala)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:262)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)3-NH2; (SEQ
ID NO:263) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID
NO:264)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-Tyr-Gly-(Arg)5-Gln-( ATg)3-NH2;
(SEQ ID NO:263)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-(Arg)5-Gln-(Arg)3-NH2; (SEQ ID NO:264)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-Tyr-Gly-(Arg)5-Gln-(Arg)4-NH2; (SEQ
ID NO:265)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-Doc-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:266) Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-Tyr-Gly-(Arg)s-Gln-(Arg)4-NH2;
(SEQ ID NO:265)
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-(Doc)2-(Arg)5-Gln-(Arg)4-NH2; (SEQ ID
NO:266)
Ac-c(Cys-Glu-His-D-4-Br-Phe-Arg-Trp-Gly-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID NO:268)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID NO:269) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Ala-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID NO:269)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-l-Nal-Ala-Cys)-(Pro)2-Lys-Asp-NH2, (SEQ ID NO:269) Ac-c(Cys-Glu-His-D-2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys- Asp-NH2; (SEQ ID NO:210) Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-/-Ala-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID NO-.270)
Ac-c(Cys-Glu-His-D-2-Nal-Arg-2-Nal-Aib-Cys)-(Pro)2-Lys-Asp-NH2; (SEQ ID NO:270) c[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:271) c[Hydantoin(C(O)-(hCys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:271) c[Hydantoin(C(O)-(Cys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH2; (SEQ ID NO:272) c[Hydantoin(C(O)-(hCys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH2; (SEQ ID NO:272) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:273) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH2; (SEQ ID NO:273) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH2; (SEQ ID NO:273) c[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH2; (SEQ ID NO:273) c[Hydantoin(C(O)-(Asp-His))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Asp-His))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-A3c))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-A5c))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-A6c))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-A3c))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Asp-A5c))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Asp-A6c))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin (C(O)-(Asp-A5c))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Asp-Aic))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-Apc))-D-Phe-Arg-Trp-Lys]-NH2; (SEQ ID NO:274) c[Hydantoin(C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Asp-Apc))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin-(C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin-(C(O)-(Asp-Apc))-D-2-Nal-Arg-Trp-Lys]-NH2; (SEQ ID NO:275) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH2; (SEQ ID NO:276) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH2; (SEQ ID NO:276) c[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH2; (SEQ ID NO:276) c[Hydantoin(C(O)-(Glu-His))-D-Phe-Arg-Trp-Dap]-NH2; (SEQ ID NO:277)
Hydantoin(C(O)-(Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:278)
Hydantoin(C(O)-(Nle-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:278) Hydantoin(C(O)-(Gly-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:278)
Hydantoin(C(O)-(Nle-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279)
Hydantoin(C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279)
Hydantoin(C(O)-(Nle-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID
NO:280)
Hydantoin(C(O)-(Gly-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH2; (SEQ ID
NO:280) Hydantoin(C(O)-(Ala-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279)
Hydantoin(C(O)-(D-Ala-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279)
Hydantoin(C(O)-(Aib-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279)
Hydantoin(C(O)-(Val-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279)
Hydantoin(C(O)-(Ile-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279)
Hydantoin(C(O)-(Leu-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2, (SEQ ID NO:279) Hydantoin(C(O)-(Gly-Gly))-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID
NO:281)
Hydantoin(C(O)-(Nle-Gly))-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID
NO:281) Hydantom(C(O)-(D-Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:278)
Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:279)
Hydantoin(C(O)-(Arg-Gly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:279)
Hydantoin(C(O)-(D-Arg-Gly))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID
NO:282)
Hydantoin(C(O)-(Arg-Gly))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID
NO:282) Hydantoin(C(O)-(Ala-Nle))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:283)
Hydantoin(C(O)-(Val-Nle))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:283)
Hydantoin(C(O)-(Gly-Nle))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:283)
Hydantoin(C(O)-(A6c-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:284)
Hydantoin(C(O)-(Gly-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:284) Hydantoin(C(O)-(Ala-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:284)
Hydantoin(C(O)-(D-Ala-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:284)
HydantoiB(C(O)-(Val-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ro NO:284) Hydantoin(C(O)-(Leu-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:284)
Hydantoin(C(O)-(Cha-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:284) Hydantoin(C(O)-(Aib-Nle))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:284)
Hydantoin(C(O)-(Gly-Arg))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:285)
Hydantoin(C(O)-(Gly-Arg))-c(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO:285)
Hydantoiri(C(O)-(Gly-Arg))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:286)
Hydantoin(C(O)-(Gly-Arg))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID
NO:286) Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:287)
Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:288)
Hydantoin(C(O)-(Gly-D-Arg))-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH2; (SEQ ID NO:288)
Hydantoin(C(O)-(Nle-Ala))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID
NO:289) c[Hydantoin(C(O)-(Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2/ (SEQ ID NO:290) c[Hydantoin(C(O)-(Nle-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(D-Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID
NO:290) c[Hydantoin(C(O)-(Aib-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID
NO:290) c[Hydantoin(C(O)-(Val-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydant0in(C(O)-(Abu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID
NO:290) c[Hydantoin(C(O)-(Leu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(Ile-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(Cha-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(A6c-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(Phe-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(Gly-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:290) c[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH2; (SEQ ID NO:291) Ac-Tyr-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-2-Nal-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-l-Nal-Arg-c(Cys-D-Ala-His-DPhe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-Phe-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-Trp-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) Ac-Pff-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) H-His-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:293) Ac-His-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH2; (SEQ ID NO:292) or a pharmaceutically acceptable salt thereof.
3. The method according to claim 2, wherein said compound is Ac-Arg-c(Cys-D-Ala- His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO:50) or a pharmaceutically acceptable salt thereof.
4. The method according to claim 2, wherein said compound is Hydantoin(C(O)- (Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO:278) or a pharmaceutically acceptable salt thereof.
5. The method according to any one of claims 1-4, wherein said subject is obese.
6. The method according to any one of claims 1-4 wherein said subject is overweight.
7. The method according to any one of claims 1-4, wherein said subject is normal weight.
8. The method according to any one of claims 1-4, wherein said subject is lean.
9. The method according to claim 5, wherein said obese subject suffers from type II diabetes.
10. The method according to claim 6, wherein said overweight subject suffers from type II diabetes.
11. The method according to claim 7, wherein said normal weight subject suffers from type II diabetes.
11. The method according to claim 8, wherein said lean subject suffers from type II diabetes.
13. The method according to claim 1, wherein said peripheral administration is oral, subcutaneous, intraperitoneal, intramuscular, intravenous, rectal, transdermal or intranasal.
14. The method according to claim 13, wherein said administration is continuous, hourly, four times daily, three time daily, twice daily, once daily, once every other day, twice weekly, once weekly, once every two weeks, once a month, or once every two months.
15. The method according to claim 14, wherein said administration is continuous.
16. The method according to claim 14, wherein said administration is once daily.
17. The method according to claim 14, wherein said administration is once weekly
18. The method according to claim 14, wherein said administration is once every two weeks.
19. The method according to claim 14, wherein said administration is once a month.
20. The method according to claim 14, wherein said administration is once every two months.
21. The method according to any one of claims 1-4, wherein said peripheral administration of an effective amount of a melanocortin receptor 4 agonist to treat said insulin resistance in a subject need thereof also reduces the body weight of said subject in need thereof.
22. The method according to claim 21, wherein said compound is Ac-Arg-c(Cys-D- Ala-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO:50) or a pharmaceutically acceptable salt thereof.
23. The method according to claim 21, wherein said compound is Hydantoin(C(O)- (Arg-Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO:278) or a pharmaceutically acceptable salt thereof.
24. The method according to any one of claims 21-23, wherein said subject is obese.
25. The method according to any one of claims 21-23, wherein said subject is overweight.
26. The method according to claim 24, wherein said obese subject suffers from type II diabetes.
27. The method according to claim 25, wherein said overweight subject suffers from type II diabetes.
28. The method according to claim 21, wherein said peripheral administration is oral, subcutaneous, intraperitoneal, intramuscular, intravenous, rectal, transdermal or intranasal.
29. The method according to claim 28, wherein said administration is continuous, hourly, four times daily, three time daily, twice daily, once daily, once every other day, twice weekly, once weekly, once every two weeks, once a month, or once every two months.
30. The method according to claim 29, wherein said administration is continuous.
31. The method according to claim 29, wherein said administration is once daily.
32. The method according to claim 29, wherein said administration is once weekly
33. The method according to claim 29, wherein said administration is once every two weeks.
34. The method according to claim 29, wherein said administration is once a month.
35. The method according to claim 29, wherein said administration is once every two months.
PCT/US2008/012490 2007-11-05 2008-11-05 Use melanocortins to treat insulin sensitivity WO2009061411A2 (en)

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CA2704651A CA2704651C (en) 2007-11-05 2008-11-05 Use of melanocortins to treat insulin sensitivity
BRPI0819188-3A BRPI0819188B1 (en) 2007-11-05 2008-11-05 USE OF MELANOCORTINES FOR THE PREPARATION OF A DRUG TO TREAT INSULIN RESISTANCE
AU2008325194A AU2008325194B2 (en) 2007-11-05 2008-11-05 Use melanocortins to treat insulin sensitivity
DK08846334.4T DK2214693T3 (en) 2007-11-05 2008-11-05 Use of melanocortins in the treatment of insulin sensitivity
EP15179111.8A EP2979703B1 (en) 2007-11-05 2008-11-05 Use of melanocortins to treat insulin sensitivity
CN2008801238931A CN101980717A (en) 2007-11-05 2008-11-05 Use melanocortins to treat insulin sensitivity
PL08846334T PL2214693T3 (en) 2007-11-05 2008-11-05 Use of melanocortins to treat insulin sensitivity
KR1020107012327A KR101290623B1 (en) 2007-11-05 2008-11-05 Use of melanocortins to treat insulin sensitivity
NZ585131A NZ585131A (en) 2007-11-05 2008-11-05 Use melanocortins to treat insulin sensitivity
ES08846334.4T ES2555522T3 (en) 2007-11-05 2008-11-05 Use of melanocortins to treat insulin sensitivity
EP08846334.4A EP2214693B1 (en) 2007-11-05 2008-11-05 Use of melanocortins to treat insulin sensitivity
KR1020137011647A KR101662044B1 (en) 2007-11-05 2008-11-05 Use melanocortins to treat insulin sensitivity
KR1020147036380A KR20150013339A (en) 2007-11-05 2008-11-05 Use melanocortins to treat insulin sensitivity
JP2010532076A JP2011502987A (en) 2007-11-05 2008-11-05 Use of melanocortins to treat insulin hypersensitivity
US12/740,917 US9155777B2 (en) 2007-11-05 2008-11-05 Use of melanocortins to treat insulin sensitivity
IL205554A IL205554A (en) 2007-11-05 2010-05-05 Composition for treating insulin resistance comprising melanocortins
HK11100510.8A HK1146242A1 (en) 2007-11-05 2011-01-19 Use of melanocortins to treat insulin sensitivity
US14/844,128 US9439943B2 (en) 2007-11-05 2015-09-03 Use of melanocortins to treat insulin sensitivity
US15/242,866 US9827286B2 (en) 2007-11-05 2016-08-22 Use of melanocortins to treat insulin sensitivity
IL249998A IL249998B (en) 2007-11-05 2017-01-09 Composition for use in treating insulin resistance comprising a hydantoin derivative
US15/801,432 US20180303899A1 (en) 2007-11-05 2017-11-02 Use of Melanocortins to Treat Insulin Sensitivity
US16/225,189 US20190111105A1 (en) 2007-11-05 2018-12-19 Use of Melanocortins to Treat Insulin Sensitivity
US17/831,887 US20220339239A1 (en) 2007-11-05 2022-06-03 Use of melanocortins to treat insulin sensitivity

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EP2148692A2 (en) * 2007-05-25 2010-02-03 Ipsen Pharma S.A.S. Melanocortin receptor ligands modified with hydantoin
EP2979703A1 (en) 2007-11-05 2016-02-03 Ipsen Pharma S.A.S. Use of melanocortins to treat insulin sensitivity
US8846601B2 (en) 2009-06-08 2014-09-30 Palatin Technologies, Inc. Melanocortin receptor-specific peptides
US10632171B2 (en) 2009-06-08 2020-04-28 Palatin Technologies, Inc. Melanocortin receptor-specific peptides
US10179804B2 (en) 2009-06-08 2019-01-15 Palatin Technologies, Inc. Melanocortin receptor-specific peptides
US9458201B2 (en) 2009-06-08 2016-10-04 Palatin Technologies, Inc. Melanocortin receptor-specific heptapeptides
US9273098B2 (en) 2009-06-08 2016-03-01 Palatin Technologies, Inc. Lactam-bridged melanocortin receptor-specific peptides
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EP2461681A4 (en) * 2009-08-05 2013-04-24 Ipsen Pharma Sas Use of melanocortins to treat dyslipidemia
EP2473518A4 (en) * 2009-08-31 2013-06-12 Tensive Controls Inc Stabilized melanocortin ligands
US8541545B2 (en) 2009-08-31 2013-09-24 Tensive Controls Inc. Stabilized melanocortin ligands
EP2473518A2 (en) * 2009-08-31 2012-07-11 Tensive Controls, Inc. Stabilized melanocortin ligands
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EP2501225A1 (en) * 2009-11-16 2012-09-26 Ipsen Pharma S.a.S. Pharmaceutical compositions of melanocortin receptor ligands
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JP2013510879A (en) * 2009-11-16 2013-03-28 イプセン ファルマ ソシエテ パール アクシオン サンプリフィエ Pharmaceutical composition of melanocortin receptor ligand
US10711039B2 (en) 2009-11-23 2020-07-14 Palatin Technologies, Inc. Melanocortin receptor-specific peptide with C-terminal naphthylalanine
US8933194B2 (en) 2009-11-23 2015-01-13 Palatin Technologies, Inc. Melanocortin-1 receptor-specific linear peptides
US9447148B2 (en) 2009-11-23 2016-09-20 Palatin Technologies, Inc. Melanocortin-1 receptor-specific cyclic peptides
US9580466B2 (en) 2009-11-23 2017-02-28 Palatin Technologies, Inc. Melanocortin-1 receptor-specific linear peptides
US8877890B2 (en) 2009-11-23 2014-11-04 Palatin Technologies, Inc. Melanocortin-1 receptor-specific cyclic peptides
US10017539B2 (en) 2009-11-23 2018-07-10 Palatin Technologies, Inc. Melanocortin-1 receptor-specific cyclic hexapeptides
US10106578B2 (en) 2009-11-23 2018-10-23 Palatin Technologies, Inc. Melanocortin-1 receptor-specific linear peptides
WO2012172433A3 (en) * 2011-06-14 2013-01-31 Ipsen Pharma S.A.S. A sustained -release composition containing a melanocortin receptor ligand as the active ingredient
CN103608003A (en) * 2011-06-14 2014-02-26 益普生制药股份有限公司 A sustained-release composition containing a melanocortin receptor ligand as the active ingredient
US9415012B2 (en) 2011-06-14 2016-08-16 Ipsen Pharma S.A.S. Sustained-release composition containing peptides as active ingredient
US10167312B2 (en) 2011-12-29 2019-01-01 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
US9845339B2 (en) 2011-12-29 2017-12-19 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
US10954268B2 (en) 2011-12-29 2021-03-23 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
US11702448B2 (en) 2011-12-29 2023-07-18 Rhythm Pharmaceuticals, Inc. Method of treating melanocortin-4 receptor-associated disorders in heterozygous carriers
US9534018B2 (en) 2012-03-13 2017-01-03 Tensive Controls Inc. Melanocortin analogs having enhanced activity and transport
US10829519B2 (en) 2015-09-18 2020-11-10 Wake Forest University Health Sciences Angiotensin (1-7) analogs and methods relating thereto
US11124541B2 (en) * 2016-10-18 2021-09-21 Regents Of The University Of Minnesota Chimeric melanocortin ligands and methods of use thereof
US11332499B2 (en) 2018-08-16 2022-05-17 Regents Of The University Of Minnesota Cyclic peptides and methods of use thereof

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