WO2008020778A1 - Famille de peptides dotés d'une activité analgésique - Google Patents

Famille de peptides dotés d'une activité analgésique Download PDF

Info

Publication number
WO2008020778A1
WO2008020778A1 PCT/RU2006/000404 RU2006000404W WO2008020778A1 WO 2008020778 A1 WO2008020778 A1 WO 2008020778A1 RU 2006000404 W RU2006000404 W RU 2006000404W WO 2008020778 A1 WO2008020778 A1 WO 2008020778A1
Authority
WO
WIPO (PCT)
Prior art keywords
dldhpro
tur
tyr
ser
pro
Prior art date
Application number
PCT/RU2006/000404
Other languages
English (en)
Russian (ru)
Inventor
Lyudmila Yurievna Alfeeva
Lyudmila Alexandrovna Andreeva
Tatyana Alexandrovna Voronina
Lyudmila Sergeevna Guzevatykh
Tatyana Georgievna Emelyanova
Nikolay Fedorovich Myasoedov
Sergei Borisovich Seredenin
Original Assignee
Institut Molekulyarnoi Genetiki Rossiiskoi Akademii Nauk (Img Ran)
Gosudarstvennoe Uchrezhdenie Nauchno-Issledovatelsky Institut Farmakologii Imeni V.V. Zakusova Rossiiskoi Akademii Meditsinskikh Nauk (Gu Nii Farmakologii Imeni V.V. Zakusova Ramn)
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.)
Filing date
Publication date
Application filed by Institut Molekulyarnoi Genetiki Rossiiskoi Akademii Nauk (Img Ran), Gosudarstvennoe Uchrezhdenie Nauchno-Issledovatelsky Institut Farmakologii Imeni V.V. Zakusova Rossiiskoi Akademii Meditsinskikh Nauk (Gu Nii Farmakologii Imeni V.V. Zakusova Ramn) filed Critical Institut Molekulyarnoi Genetiki Rossiiskoi Akademii Nauk (Img Ran)
Priority to PCT/RU2006/000404 priority Critical patent/WO2008020778A1/fr
Publication of WO2008020778A1 publication Critical patent/WO2008020778A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1021—Tetrapeptides with the first amino acid being acidic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1008—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to the use of peptides of the general formula A-B-Tyr-Pro (DPro, dHPro, DdHPro, DLdHPro, Hyp) -B-X below as analgesic analgesics.
  • narcotic morphine and structures close to it
  • non-narcotic analgesics derivatives of salicylic acid, pyrazolone, aniline, etc.
  • Endogenous ligands of peptide nature responsible for the physiological analgesic effects of enkephalins and endorphins, are known in mammals.
  • another class of endogenous peptides - dinorphins, in particular dermorphin [Emelyanova T.G.,
  • the cited amino acid sequences possessing analgesic activity have a common pattern, namely, the presence of the Tyr-Pro peptide sequence (DPro, dHPro, DdHPro, DLdHPro, Nur) in the 1,2 or 2,3 positions of the above peptides in the structure.
  • DPro, dHPro, DdHPro, DLdHPro, Nur the Tyr-Pro peptide sequence
  • A-B-Tyr-Pro (DPro, d ⁇ r GmbH, Dd ⁇ r consumer, DLd ⁇ r technically, Hyp) -BX (I), where A is O, -AIa, -Asp, -GIu, -Phe, -GIy, -His, -Pe, -Lus, -Leu, -Met, -Pro, -Arg, -Ser, -Thr,
  • X is OH, -OCH 3 , -NH 2 .
  • the invention relates to the field of physiology and pharmacology for the creation of new drugs and may find application in medicine.
  • the technical result achieved by the present invention is the creation of new peptides that meet the general formula (I), the identification of their useful analgesic properties and the directed development of medicinal products based on them preparations.
  • the specified technical result is achieved in that it allows the directional synthesis of various peptide sequences corresponding to the general formula (I) according to the general scheme.
  • Tyr-Gly-Tyr-DLd ⁇ r Williams- ⁇ modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier modifier- ⁇
  • Tyr-Ala-Tyr-DLd ⁇ r Albany-Gl dilemma Tyr-Ala-Tyr-DLdHPro-Gly-NH 2 ⁇ ur-Ala-Tur-DLd ⁇ r-Gl dilemma- ⁇
  • Tur-Ala-Tur-DLd ⁇ r Geneva-Ala-Tur-DLd ⁇ r
  • Tur-Ala-Tur-DLd ⁇ r Geneva-Ala-Tur-DLd ⁇ r
  • Ala-Glu-Tur-DLdHPro-GI involves Ala-Gly-Tyr-DLdHPro-Gly-NH 2 Ala-Glu-Tur-DLdHrro-GIu-OCH
  • Ser-Il Pain-Tur-DLd ⁇ r
  • Ser-Il Springfield-Tur-DLd ⁇ r
  • Val-Val-Tur-DLdHPro-Ala Val-VaI-Tyr-DLdHPro-Ala-NH 2 ⁇ a-Va-Tur-DLdHPro-Ala-OCH
  • Val-Val-Tur-DLdHPro-Glu Val-Val-Tyr-DLdHPro-Glu-NH 2 v ⁇ al-Val-Tur-DLdHPro-Glu-OCH
  • Val-Val-Tur-DLd ⁇ r Ltd., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Inc., Japan, Vapentad ⁇ , Vapentad, Vapentad, Inc., Vap-Val-Tur-DLd ⁇ r, Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc
  • Val-Val-Tur-DLd ⁇ r Williams-Lus Val-Val-Tyr-DLdHPro-Lys-NH 2 Val-Val-Tur-DLd ⁇ rro-Lus-OCH
  • Val-Val-Tur-DLd ⁇ r Desired Val-Val-Tur-DLd ⁇ r
  • Val-Val-Tur-DLd ⁇ r Desired Val-Val-Tur-DLd ⁇ r
  • Val-Val-Tur-DLd ⁇ r Desired Val-Val-Tur-DLd ⁇ r
  • Val-Val-Tur-DLd ⁇ r Desired Val-Val-Tur-DLd ⁇ r
  • Val-Val-Tyr-DLd ⁇ r Summary- ⁇ Val-Val-Tyr-DLdHPro-Trp- ⁇ 2 Val-Val-Tur-DLd ⁇ r- ⁇ modifier
  • Val-Val-Tur-DLdHPro-Tur Val-Val-Tyr-DLdHPro-Tyr-NH 2 Val-Val-Tur-DLdHr-Tur-OCH
  • Lus-Arg-Tur-DLdHPro-Il Korean Lys-Arg-Tyr-DLdHPro-1 Ie-NH 2 Lus-Arg-Tur-DLdHPro-I Ie-OCH 3
  • Tur-Il-Tur-DLd ⁇ r Albany-Asr Tur-Il
  • Tur-Il-Tur-DLd ⁇ r Albany-Asr Tur-Il
  • Tur-Il Springfield-Tur-DLd ⁇ r-ASp-NH 2
  • Tur-Il Springfield-Tur-DLd ⁇
  • Tur-Ilé-Tug-DLd ⁇ r 6- ⁇
  • Tur-Il-Tur-DLd ⁇ Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc., Inc.,
  • Tur-Il-Tur-DLd ⁇ r Albany-Il-Tur-DLd ⁇ r
  • Ser-Asr-Tug-DLd ⁇ r must-II
  • Ser-Asr-Tur-DLd ⁇ r must-Il
  • Ser-Asr-Tur-DLd ⁇ r Although- ⁇ opposition attend Ser-Asr-Tur-DLd ⁇ r?-Tur-N H 2 Ser-Asr-Tur-DLd ⁇ r arise-Tur- ⁇
  • Pro-Va ⁇ -Tur-DLdHPro-GI involves Pro-VaI-Tyr-DLdHPro-Gly-NH 2 ⁇ ro-Val-Tur-DLdHPro-Glu-OCH
  • Tyr-Leu-Tyr-DLd ⁇ r Albany-Leu-Tyr-DLd ⁇ r
  • Tyr-Leu-Tyr-DLd ⁇ r desires to be kept in the middle position.
  • Tyr-Leu-Tyr-DLd ⁇ r desires to be kept in the middle position.
  • Tyr-Leu-Tyr-DLd ⁇ r Williams- ⁇ is Tyr-Leu-Tyr-DLdHPro-His-NH 2 ⁇ ur-Leu-Tur-DLd ⁇ r- ⁇ is- ⁇
  • Tyr-Leu-Tyr-DLd ⁇ r Although-Leu-Tyr-DLd ⁇ r, Ltd- ⁇ modifier modifier Tyr-Leu-Tyr-DLdHPro-Trp-NH 2 ⁇ ur-Leu-Tur-DLd ⁇ rschreib- ⁇ modifier modifier- ⁇
  • Val-Pro-Tyr-DLdHPro-Asp Val-Pro-Tyr-DLdHPro-Asp-NH 2 Val-Pro-Tyr-DLdHPro-Asp-OCH 3
  • Val-Pro-Tur-DLdHPro-Glu Val-Pro-Tyr-DLdHPro-G! Y-NH 2 Val-Pro-Tur-DLdHr-Glu-OCH
  • Val-Pro-Tur-DLdHPro-Tur Val-Pro-Tyr-DLdHPro-Tyr-NH 2 Val-Pro-Tur-DLdHr-Tur-OCH
  • Val-GIu-Tur-DLdHPro-Ala VaI-Gly-Tyr-DLdHPro-AIa-NH 2
  • Val-Glu-Tur-DLdHPro-Asr Val-Gly-Tyr-DLdHPro-Asp- ⁇ H 2 Va-Glu-Tur-DLdHPro-Asr-OCH
  • Val-Glu-Tur-DLdHPro-Phe Val-Gly-Tyr-DLdHPro-Phe-NH 2 Val-Glu-Tur-DLdHPro-Phe-OCH
  • Val-GIu-Tur-DLdHPro-His Val-Gly-Tyr-DLdHPro-His-NH 2 Val-Gly-Tyr-DLdHPro-His-OCH 3
  • Val-Glu-Tur-DLdHPro-Ser Val-Gly-Tyr-DLdHPro-Ser- 2 Val-Glu-Tur-DLdHr-Ser-OCH
  • Val-Glu-Tur-DLdHPro-Ala Val-Glu-Tyr-DLdHPro-AIa-NH 2 Val-Glu-Tur-DLdHPro-A Ia-OCH 3
  • Val-Glu-Tur-DLdHPro-Asr Val-Glu-Tyr-DLdHPgo-Asp-NH 2 Va-Glu-Tur-DLdHPro-Asr-OCH
  • Val-Glu-Tyr-DLdHPro-Phe Val-Glu-Tyr-DLdHPro-Phe-NH 2 Val-Glu-Tur-DLdHpro-Phe-OCH
  • Val-Glu-Tur-DLdHPro-His Val-Glu-Tyr-DLdHPro-His-NH 2 Val-Glu-Tur-DLdHPro-His-OCH
  • Val-Glu-Tur-DLdHPro-Pe Val-Glu-Tyr-DLdHPro-Ile-NH 2 Val-Glu-Tyr-DLdHPro-Ile-OCH 3
  • Val-Glu-Tur-DLdHPro-Met VaI-Glu-Tyr-DLdHPro-Met-NH 2 Val-GIu-Tur-DLdHr-Met-OCH
  • Val-Glu-Tur-DLdHPro-Arg Val-Glu-Tyr-DLdHPro-Arg-NH 2 Val-Glu-Tur-DLdHrr-Arg-OCH
  • Val-Glu-Tur-DLdHPro-Trr Val-Glu-Tyr-DLdHPro-Trp-NH 2 Val-Glu-Tuh-DLdHrr-Trr-OCH
  • Val-Glu-Tur-DLdHPro-Tur Val-Glu-Tyr-DLdHPro-Tyr-NH 2 Val-Glu-Tur-DLdHr-Tur-OCH
  • Met-Met-Tur-DLd ⁇ r Tol, Met-Met-Tur-DLd ⁇ r must-I Ie Met-Met-Tyr-DLdHPro- ⁇ e-NH 2 Met-Met-Tur-DLd ⁇ r must-Il flesh- ⁇
  • Met-Met-Tur-DLd ⁇ r erie-Met-Tur-DLd ⁇ r
  • Met-Met-Tur-DLd ⁇ r erie-Met-Tur-DLd ⁇ r
  • Met-Met- ⁇ ur-DLd ⁇ r erie-Met-Tur-DLd ⁇ r
  • Met-Met-Tur-DLdHPro-Met Met-Met-Tyr-DLdHPro-Met-NH 2 Met-Met-Tur-DLdHPro-Met-OCH Met-Met-Tur-DLd ⁇ r Ltd- ⁇ convinced Met-Met-Tyr-DLdHPro-Pro-NH 2 ⁇ et-Met-Tur-DLd ⁇ r
  • Met-Met-Tur-DLd ⁇ r Korean-V Corporation's Met-Met-Tur-DLd ⁇ r-VaI-NH 2 Met-Met-Tur-DLd ⁇ r-VaI-OCH 3
  • Met-Il-Tur-DLd ⁇ r Albany-Glu Met-IIe-Tyr-DLdHPro-Glu-NH 2 ⁇ et-Il Skin-Tur-DLd ⁇ modifierr-Glu- ⁇
  • Met-Il To-Tur-DLd ⁇ r
  • et-II To-Tur-DLd ⁇ modifierr
  • Met-Il To-Tur-DLd ⁇ r
  • Met-Ile-Tyr-DLdHPro-Gly-NH 2 Att- ⁇ , wishes-Tur-DLd ⁇ r
  • Met-Il To-Tur-DLd ⁇ r
  • Met- ⁇ To-Tur-DLd ⁇ r
  • Met- ⁇ To-Tyr-DLdHPro-Lys-NH 2 ⁇
  • Statt-I To-Tur-DLd ⁇ r
  • Met-Il-Tur-DLd ⁇ r desires-Met Met-II Canal-Tur-DLd ⁇ r and-Met-N ⁇ Met- ⁇ mecanic-Tyr-DLdHPro-Met-OCH 3
  • Met-Il To-Tur-DLd ⁇ r
  • To-Tur-DLd ⁇ r To-Tur-DLd ⁇ r
  • Ala-Ser-Tur-DLdHPro-Il Korean Ala-Ser-Tyr-DLdHPro-IIe-NH 2 Ala-Ser-Tur-DLdHPro-IIe-OCH-,
  • Ala-Ala-Tur-DLdHPro-Asr Ala-AIa-Tyr-DLdHPro-Asp-NH 2 Ala-Ala-Tur-DLdHPro-Asr-OCH
  • the peptides of formula (I) were synthesized by peptide chemistry, both in solution and by solid-phase synthesis using L and D amino acids, as well as L, D and DL dehydro-amino acids (3,4-dehydro-amino acid in formula (I) , in the tables and examples given is indicated by dHPrutton).
  • Table 2 shows the peptides of formula (I) synthesized by peptide chemistry in solution.
  • the synthesis of the tripeptide HCl-H-Tyg-3,4-DLdHPro-Ser-OCH3 was carried out by condensation of the dipeptide DiBoc-Tyr-3,4-DLdHPro and HCl-H-Seg-OCH 3 using peptide chemistry in solution. Fragments were synthesized using tetrabutylammonium salts (TBA) and the activated ester method. Evaporation of the solutions was carried out on a vacuum evaporator at 40 ° C.
  • TSA tetrabutylammonium salts
  • DiBoc-Tyr-3,4-DLdHPgo 1.32 g (2.76 mmol) was dissolved in 20 ml of acetonitrile, an excess of (1,3) N-hydroxysuccinimide 412.8 mg (3.59 mmol) was added, cooled to 0 ° C and an excess of (1.3) DCCH was added 810.88 mg (3.59 mmol).
  • DCCH was added 810.88 mg (3.59 mmol).
  • HPLC Results Zorbach Column SB-AQ Cl 8, 4.6 x 150 mm; flow rate 1 ml / min; eluent 5% MeOH - 50 mM buff, pH 2.8), linear gradient, temperature 30 ° C, pressure 9.0 MPa, exit time 7.73 min.
  • Example 2 Table 3 shows examples of the synthesis of peptides by the automatic solid-phase method.
  • the peptides shown in Table 3 were synthesized by the automatic solid-phase method according to the Fmoc scheme on the Rink polymer (4- (2,4-dimethoxyphenyl-fluorenylmethoxy-aminomethyl) phenoxypolyistol, 0.5 mmol of amino groups per 1 g of the polymer) using the HEPTDI method. Peptides were cleaved from the polymer and released with a mixture of TFA: m-crezole (95: 5).
  • the peptides were purified using reverse phase HPLC (Juriteg Cis column (10x250 mm) in the following acetonitrile gradient: 5 min at 2%, then a linear gradient from 2 to 60% in 50 min in 0.1% trifluoroacetate buffer at a flow rate of 4 ml / min Peptides were characterized using mass spectrometry (MALDI).
  • MALDI mass spectrometry
  • Tail-off test - tilil flisk (D'Amor, 1941). The animal was placed in an individual plastic chamber, the tail was immersed 5 cm in a vessel with water with a temperature of 55 ⁇ 1 ° C. The tail jerk reflex closes at the level of the spinal cord.
  • the latent period of getting rid of the pain stimulus was recorded - the time period (sec) during which the animal pulled its tail out of the water completely. The maximum time for presentation of a pain stimulus is 30 seconds.
  • the initial pain sensitivity was determined as the arithmetic mean of the indicators recorded at 60, 40, and 20 minutes before injection. The latent period of getting rid of the pain stimulus was fixed 20, 40, and 60 120 minutes after administration.
  • Analgesic activity was evaluated by changing the latent period of the reaction according to the formula: where LP 0P - latent period of disposal after the introduction of the substance, LP IC ⁇ - the arithmetic mean of the latent periods of disposal before the introduction of the substance.
  • Tyr-Pro-Ser-NH 2 a significant extension of the reaction time for 90 minutes after injection.
  • Tur-Pro-Ser-OCH3 and Tyr-Pro-Lys-NH 2 caused an analgesic effect for one hour.
  • Effect DLdNRro-Tyr-Ser-OCH, Tyr-dHPro-Ser-NH 2 was developed 40 min after administration and lasted for up to 60 minutes at DLdNRro-Tyr-Ser-OCH and up to 90 minutes at Tur- dHPro-Ser-NH 2.
  • Tyr-DPro-Ser-OCH 3 caused an analgesic reaction at 20 and 40 minutes after administration.
  • Glu-Tyr-DPro-Ser-NH 2 possessed the greatest analgesic activity. An increase in the latent period of the reaction was observed within 90 minutes of observation.
  • Tyr-Pro-GIy-Pm-NH 2 and Tyr-Tyr-Pro-Ser-NH 2 lengthened the latent period of tail withdrawal during the 60 minutes of observation.
  • the effect of Ala-Tur-DPro-Seg-NH and DAla-Tur-DPro-Ser-NH began at 40 minutes after administration and lasted at Ala-Tur-DPro-Ser-NH for up to 60 minutes, and DAla-Tyr-DPro-Ser -NH 2 - up to 90 minutes.
  • Met-Tyr-DPro-Ser-NH 2 did not significantly change the latent period of the tail withdrawal reaction.
  • a change in amino acid residues around the Tur-Pro sequence affects analgesic activity.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Separation Using Semi-Permeable Membranes (AREA)

Abstract

La présente invention peut être utilisée dans le domaine de la physiologie et de la pharmacologie pour mettre au point de nouvelles préparations médicinales, ainsi qu'en médecine. L'invention se rapporte à la synthèse de peptides de formule générale (I), et à des peptides de formule générale A-B-Tyr-Pro (DPro, dHPro, DdHPro, DLdhPro, Hyp)-C-X, dans laquelle : A représente O, -Ala, -Asp, -Glu, -Phe, -His, -Ile, Lys, -Leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; B représente O, -Ala, -Asp, -Glu, -Phe, -His, -Ile, Lys, -Leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; C représente O, -Ala, -Asp, -Glu, -Phe, -His, -Ile, Lys, -Leu, -Met, -Pro, -Arg, -Ser, -Thr, -Val, -Trp, -Tyr; et X représente OH, -OCH3, -NH2. L'invention concerne également l'utilisation desdits peptides pour mettre au point de nouvelles préparations dotées d'une activité analgésique.
PCT/RU2006/000404 2006-07-31 2006-07-31 Famille de peptides dotés d'une activité analgésique WO2008020778A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/RU2006/000404 WO2008020778A1 (fr) 2006-07-31 2006-07-31 Famille de peptides dotés d'une activité analgésique

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/RU2006/000404 WO2008020778A1 (fr) 2006-07-31 2006-07-31 Famille de peptides dotés d'une activité analgésique

Publications (1)

Publication Number Publication Date
WO2008020778A1 true WO2008020778A1 (fr) 2008-02-21

Family

ID=39082255

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/RU2006/000404 WO2008020778A1 (fr) 2006-07-31 2006-07-31 Famille de peptides dotés d'une activité analgésique

Country Status (1)

Country Link
WO (1) WO2008020778A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014021737A1 (fr) * 2012-08-03 2014-02-06 Tatyana Georgievna Emelyanova Préparation pharmaceutique à base de dipeptide tyr-pro présentant une action anti-inflammatoire, antibactérienne et thérapeutique contre les blessures et les brûlures
WO2022099123A1 (fr) * 2020-11-06 2022-05-12 The Medical College Of Wisconsin, Inc. Inhibiteurs peptidiques de la protéine 1 de fission mitochondriale humaine et méthodes d'utilisation

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3047596A1 (de) * 1980-12-17 1982-07-22 Victor Dipl.- Chem. 8000 München Brantl Pharmakologisch aktive dipeptide
US5338668A (en) * 1990-12-27 1994-08-16 Nisshin Flour Milling Co., Ltd. Opioid peptides derived from wheat proteins
RU2043769C1 (ru) * 1994-05-17 1995-09-20 Дейгин Владислав Исакович Способ получения пептида
JP2000095794A (ja) * 1998-09-22 2000-04-04 Itoham Foods Inc エンケファリン分解酵素の阻害剤
RU2198178C2 (ru) * 1997-01-07 2003-02-10 Праймамедик Лтд. Пептид-иммунорегулятор (варианты), лекарственное средство, включающее пептид-иммунорегулятор
JP2003267994A (ja) * 2002-03-11 2003-09-25 Suetsuna Yoko 新規なペプチドおよびアンジオテンシン変換酵素阻害剤
RU2286169C1 (ru) * 2005-04-18 2006-10-27 Институт Молекулярной Генетики Российской Академии Наук (Имг Ран) Семейство пептидов, обладающее анальгетической активностью

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3047596A1 (de) * 1980-12-17 1982-07-22 Victor Dipl.- Chem. 8000 München Brantl Pharmakologisch aktive dipeptide
US5338668A (en) * 1990-12-27 1994-08-16 Nisshin Flour Milling Co., Ltd. Opioid peptides derived from wheat proteins
RU2043769C1 (ru) * 1994-05-17 1995-09-20 Дейгин Владислав Исакович Способ получения пептида
RU2198178C2 (ru) * 1997-01-07 2003-02-10 Праймамедик Лтд. Пептид-иммунорегулятор (варианты), лекарственное средство, включающее пептид-иммунорегулятор
JP2000095794A (ja) * 1998-09-22 2000-04-04 Itoham Foods Inc エンケファリン分解酵素の阻害剤
JP2003267994A (ja) * 2002-03-11 2003-09-25 Suetsuna Yoko 新規なペプチドおよびアンジオテンシン変換酵素阻害剤
RU2286169C1 (ru) * 2005-04-18 2006-10-27 Институт Молекулярной Генетики Российской Академии Наук (Имг Ран) Семейство пептидов, обладающее анальгетической активностью

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DATABASE CA [online] KISO Y. ET AL.: "Synthesis and activity of opioid peptides", accession no. STN Database accession no. (99:105680) *
DATABASE CA [online] LOTTSPEICH F. ET AL.: "Novel opioid peptides derived from casein (beta-casomorphins). III. Synthetic peptides corresponding to components from bovine casein peptone", accession no. STN Database accession no. (94:175513) *
DATABASE CA [online] YOSHIKAWA M. ET AL.: "Orally active memory-enhancing peptides obtained by designing bioactive peptides derived from food proteins", accession no. STN Database accession no. (132:102724) *
HOPPE-SEYLER'S ZEITSCHRIFT FUER PHYSIOLOGISCHE CHEMIE, vol. 361, no. 12, December 1980 (1980-12-01), pages 1835 - 1839 *
PEPTIDE CHEMISTRY, vol. 20TH, 1983, pages 245 - 250 *
PEPTIDE SCIENCE: PRESENT AND FUTURE, PROCEEDINGS OF THE INTERNATIONAL PEPTIDE SYMPOSIUM, 1ST, KYOTO, 30 November 1997 (1997-11-30) - 5 December 1997 (1997-12-05) *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014021737A1 (fr) * 2012-08-03 2014-02-06 Tatyana Georgievna Emelyanova Préparation pharmaceutique à base de dipeptide tyr-pro présentant une action anti-inflammatoire, antibactérienne et thérapeutique contre les blessures et les brûlures
WO2022099123A1 (fr) * 2020-11-06 2022-05-12 The Medical College Of Wisconsin, Inc. Inhibiteurs peptidiques de la protéine 1 de fission mitochondriale humaine et méthodes d'utilisation

Similar Documents

Publication Publication Date Title
JPH08508299A (ja) サイトカイン抑制剤
WO2008056207A1 (fr) Systèmes de libération transdermique de peptides et composés associés
CA2126697A1 (fr) Peptides opioides
WO2013149506A1 (fr) Peptide chimère à base de peptide opioïde biphaline et de neuropeptide ff et synthèse et utilisation de celui-ci
RU2286169C1 (ru) Семейство пептидов, обладающее анальгетической активностью
KR101176890B1 (ko) 단백질 결합 메토트렉사트 유도체 및 상기 유도체를 포함하는 약제
RU2538727C1 (ru) Анальгетическое средство пептидной структуры на основе тридекапептида, содержащего d-октааргининовый вектор
WO2008020778A1 (fr) Famille de peptides dotés d'une activité analgésique
CA1249100A (fr) Derives peptidiques, leur procede de preparation et les compositions les contenant
CN101448850B (zh) 免疫调节寡肽
US7183430B2 (en) Compounds which can block the response to chemical substances or thermal stimuli or mediators of inflammation of nociceptors, production method thereof and compositions containing same
EP0755942B1 (fr) Derive type n-amidino de dermorphin
MXPA05001599A (es) Compuestos de union a p-selectina.
Gach-Janczak et al. Synthesis and activity of opioid peptidomimetics with β2-and β3-amino acids
RU2264823C2 (ru) Способ и пептиды для лечения эректильной дисфункции, способ и фармацевтическая композиция с использованием указанных пептидов
CA2508129C (fr) Nouveaux peptides (-i) de x-conotoxine
ES2259812T3 (es) Derivados de (3r)-3-amino-4-carboxibutiraldehido inhibidores de la liberacion de interleuquina-1/beta.
US8642555B2 (en) Prodrugs
WO1997010261A1 (fr) Derives peptidiques
JP2918746B2 (ja) ペプチド誘導体およびその用途
RU2144038C1 (ru) Пептиды для ингибирования высвобождения пепсина, фармацевтическая композиция
Pajpanova Design, synthesis, analysis and pharmacological evaluation of neuropeptide mimetics containing unnatural amino acids
US20010007016A1 (en) Peptide derivatives
Śleszyńska et al. New bradykinin B2 receptor antagonists-influence of C-terminal segment modifications on their pharmacological properties
SU687794A1 (ru) "Октапептид,облобладающий способностьюСпЕцифичЕСКи иНгибиРОВАТь пРЕССОРНый эффЕКТи МиОТРОпНОЕ дЕйСТВиЕ АНгиОТЕНзиНА п4

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 06847392

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 06847392

Country of ref document: EP

Kind code of ref document: A1