WO2009108364A2

WO2009108364A2 - Antagonistic analogues of ghrh

Info

Publication number: WO2009108364A2
Application number: PCT/US2009/001279
Authority: WO
Inventors: Zheng Xin Dong; Daniel B. Deoliveira
Original assignee: Ipsen Pharma S.A.S.
Priority date: 2008-02-27
Filing date: 2009-02-27
Publication date: 2009-09-03
Also published as: WO2009108364A3

Abstract

There is provided a novel series of synthetic antagonistic analogues of hGHRH(l- 29)NH₂ (SEQ E) NO: 1). These analogues inhibit the activity of endogenous hGHRH on the pituitary GHRH receptors, and therefore prevent the release of growth hormone. The analogues also inhibit the proliferation of human cancers through a direct effect on the cancer cells. The inhibitory potencies of the new analogues result from replacement of various amino acids.

Description

ANTAGONISTIC ANALOGUES OF GHRH

BACKGROUND OF THE INVENTION

The present invention is directed to novel peptidyl analogues of growth hormone releasing hormone ("GHRH") that inhibit the release of growth hormone from the pituitary in mammals as well as inhibit the proliferation of cancers through direct effect on cancer cells, to therapeutic compositions containing these novel analogues of GHRH, and to methods of using same to treat mammals.

GHRH is a peptide belonging to the secretin/glucagon family of neuroendocrine and gastrointestinal hormones, a family that also includes vasoactive intestinal peptide ("VIP"), pituitary adenylate cyclase activating peptide ("PACAP") and others. The primary releasing factor is GHRH. Human GHRH ("hGHRH") is a peptide having 44 amino acids. The novel peptides of the present invention relate to analogues of hGHRH having residues 1 through 29, i.e., hGHRH(l-29)NH₂, which has the amino acid sequence:

Tyr - Ala - Asp - Ala - lie⁵ - Phe - Thr - Asn - Ser - Tyr¹⁰ - Arg - Lys -

VaI - Leu - GIy¹⁵ - GIn - Leu - Ser - Ala - Arg²⁰ - Lys - Leu - Leu - GIn - Asp²⁵ - He - Met - Ser - Arg²⁹ - NH₂ (SEQ ID NO: 1)

The best known site of production of GHRH is the hypothalamus, but it was found that various peripheral organs also synthesize it. hGHRH is also produced, sometimes in large quantities, by human malignant tissues (cancers) of diverse origin.

GHRH exerts various physiological and pathophysiological functions. Hypothalamic GHRH is an endocrine releasing hormone that, acting through specific GHRH receptors on the pituitary, regulates the secretion of pituitary growth hormone. The physiological functions of GHRH in extrapituitary tissues are less clear. However, there is increasing evidence for the role of GHRH as an autocrine/paracrine growth factor in various cancers. Splice variant ("SV") receptors for GHRH, different from those expressed in the pituitary, are present in human cancers of the lung, prostate, breast, ovary, endometrium, stomach, intestine, pancreas, kidney, and bone. See, e.g., Halmos G., et al, Proc. Natl. Acad. ScL USA, 97: 10555-10560 (2000j;^~RekasfZ., et al, Proc. Natl. Acad. Sd. USA, 97: 1^"0561-1^'056S (2000); and Schally A.V., et al, Frontiers Neuroendocrinal, 22: 248-291 (2001). The term "GHRH receptors" as used herein includes splice variants of GHRH receptors. The actions of tumoral autocrine/paracrine GHRH could be exerted on these receptors. In view of the role of GHRH as an endocrine regulator of growth hormone release, novel therapeutic strategies, based on the use of agonistic and antagonistic analogues of GHRH, have been devised for the treatment of various pathological conditions. Growth hormone is a polypeptide having 191 amino acids which stimulates the production of numerous growth factors, e.g., insulin-like growth factor 1 ("IGF-I"), and thus promotes growth of numerous tissues (e.g., skeleton, connective tissue, muscle, and viscera) and stimulates various physiological activities (e.g., stimulating the synthesis of nucleic acids and proteins, stimulating lipolysis, but suppressing urea secretion). Release of pituitary growth hormone is under the control of releasing and inhibiting factors secreted by the hypothalamus, the primary releasing factors being GHRH and ghrelin, and the main factor being somatostatin.

Growth hormone has been implicated in several diseases. One disease in which growth hormone is involved is acromegaly, in which excessive levels of growth hormone are present. The abnormally enlarged facial and extremity bones, and the cardiovascular symptoms of this disease can be treated by administering a GHRH antagonist. Further diseases involving growth hormone are diabetic retinopathy and diabetic nephropathy. The damage to the retina and kidneys respectively in these diseases, believed to be due to hypersecretion of growth hormone, results in blindness or reduction in kidney function. This damage can be prevented or slowed by administration of an effective GHRH antagonist.

In an effort to intervene in these diseases and other conditions, some investigators have attempted to control growth hormone and IGF-I levels by using analogues of somatostatin, an inhibitor of growth hormone release. However, somatostatin analogues, if administered alone, do not suppress growth hormone or IGF-I levels to a desired degree. If administered in combination with a GHRH antagonist, somatostatin analogues will suppress IGF-I levels much better.

However, the main applications of GHRH antagonists are in the field of cancer. See, e.g., Schally A. V. and Varga J.L., Trends Endocrinol. Metab., 10: 383-391 (1999); and Schally A.V., et al, Frontiers Neuroendocrinal., 22: 248-291 (2001). GHRH antagonists inhibit the proliferation of malignancies by indirect endocrine mechanisms based on the inhibition of pituitary growth hormone release and resulting in the decrease of serum levels of growth hormone and IGF-I, as well as by direct effects on the tumor tissue. Tumoral GHRH has been shown to act as an autocrine growth factor in a wide range of human cancers. Antagonistic analogues of GHRH can inhibit the stimulatory activity of GHRH and exert direct antiproliferative effects in vitro on cancer cells, and in vivo on tumors. Direct antiproliferative effects of GHRH antagonists are exerted on tumoral receptors, hi addition to the specific tumoral SV receptors for GHRH, receptors for VIP and other, as yet unidentified receptors of this family, are targets of GHRH antagonists. hi addition to endocrine inhibitory effects on serum growth hormone and IGF-I, GHRH antagonists have been found to reduce the autocrine and paracrine production of several tumor growth factors and/or downregulate their receptors. These growth factors include IGF-I, IGF-II, growth hormone, vascular endothelial growth factor ("VEGF"), and fibroblast growth factor ("FGF"). Thus, a disruption of the autocrine/paracrine stimulatory loops based on these growth factors contributes to the efficacy of GHRH antagonists as antitumor agents.

IGF-I and IGF-II are autocrine/paracrine growth factors with potent mitogenic effects on various cancers. IGF-I is also an endocrine growth factor, and elevated levels of serum IGF-I are considered an epidemiological risk factor for the development of prostate cancer, lung cancer, and colorectal cancer. The involvement of IGF-I in breast cancer, prostate cancer, colon cancer, bone tumors and other malignancies is well established. Nevertheless, autocrine/paracrine control of proliferation by IGF-II is also a major factor in many tumors. IGF-I and IGF-II exert their proliferative and anti-apoptotic effects through the common IGF- I receptor. The receptors for IGF-I are present in primary human breast cancers, prostate cancers, lung cancers, colon cancers, brain tumors, pancreatic cancers, and in renal cell carcinomas, hi several experimental cancers, such as those of the bone, lung, prostate, kidney, breast, ovary, intestine, pancreas, and brain, treatment with GHRH antagonists produces a reduction in IGF-I and/or IGF-II levels, concomitant to inhibition of tumor growth. See, e.g., Schally A.V. and Varga J.L., Trends Endocrinol. Metab., 10: 383-391 (1999); and Schally A.V., et al, Frontiers Neuroendocrinal, 22: 248-291 (2001). In some cases, the expression of IGF-I receptors was also decreased by GHRH antagonists. Thus, the disruption of endocrine and autocrine/paracrine stimulatory loops dependent on IGF-I and IGF-II contributes to the_antitumor effect of GHRH antagonists. hi MXT breast cancer model, treatment with GHRH antagonists inhibited tumor growth, reduced the mRNA level for growth hormone and the concentration of growth hormone peptide in tumors, and inhibited the mRNA expression for growth receptors. Szepeshazi K., et al, Endocrinology, 142: 4371-4378 (2001). Growth hormone was shown to act as a growth factor for MXT murine mammary carcinoma cells, MCF-7 human breast cancer cells and other tumor cell lines. Thus, the inhibitory activity of GHRH antagonists on local and serum growth hormone levels contributes to their antitumor effect. GHRH antagonists have been shown to inhibit the mRNA levels and protein concentrations of VEGF in human androgen-sensitive and androgen-independent prostate cancer models. Letsch M., et al, Proc. Natl. Acad. Sci. USA, 100: 1250-1255 (2003); and Plonowski A., et al, Prostate, 52: 173-182 (2002). And this phenomenon contributes to their antitumor effect, since VEGF plays an important stimulatory role in the neovascularization and growth of various tumors. Moreover, it was found that a GHRH antagonist inhibited the VEGF secretion and proliferation of normal murine endothelial cells, apparently through a direct effect on these cells in vitro. Siejka A., el al, Life Sci., 72: 2473-2479 (2003).

However, GHRH is known to degrade rapidly in vivo. See, e.g., Boulanger, et al, Brain Res. (1993); and Boulanger, et al, Peptides (1992). As such, there is a need for GHRH analogues having enhanced antagonistic properties and prolonged duration of action regarding the inhibition of GHRH-evoked growth hormone release, as well as the inhibition of the proliferation of human cancers through a direct effect on the cancer cells.

SUMMARY OF THE INVENTION There is provided a novel series of peptidyl analogues of hGHRH(l-29)NH₂. The analogues of the invention inhibit the activity of endogenous hGHRH, and therefore inhibit the release of growth hormone, as well as inhibit the proliferation of human cancers through a direct effect on the cancer cells. The inhibitory potencies of the new analogues result from replacement of various amino acids. Specifically, the invention relates to peptides comprising the formula (I):

(R¹R²)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-Gln-A¹⁷-A¹⁸-A¹⁹-A²⁰-

A²¹-A²²-A²³-Gln-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-R³

(I) wherein:

A¹ is Tyr or His;

A² is Ape, Aib, Act, D-Arg, D-Orn, D-Dab, D-Dap, D-VaI, D-Leu, D-Phe, D-Trp, D- Tyr, D-Ser, D-Thr, D-GIu, D-Asp, or D-AIa; A³ is Asp or Aib; A⁴ is Ala or Aib;

A⁵ is He or Ace;

A⁶ is Phe, Brp, Cpa, Cpal, or des-Phe;

A⁷ is Thr or Aib; A is Asn or Aib;

A⁹ is Ser, Aib, Amp, Arg, or hArg;

A¹⁰ is Tyr, Amp or Mop;

A¹¹ is Arg, Ape, His, or Lys(N^ε-C(O)(CH₂)_m-CH₃);

A¹² is Lys, Ape, Arg, or Lys(N^ε-C(O)(CH₂)_m-CH₃); A¹³ is VaI or Ace;

A¹⁴ is Leu or Ace;

A¹⁵ is GIy, Aib, Apn, Abu, or β-Ala;

A¹⁷ is Leu or Ace;

A¹⁸ is Ser or Aib; A¹⁹ is Ala or Aib;

A²⁰ is Arg or His;

A²¹ is Lys, Arg, or Lys(N^ε-C(O)(CH₂)_m-CH₃);

A²² is Leu or Ace;

A²³ is Leu or Ace; A²⁵ is Asp or Aib;

A²⁶ is He or Ace;

A²⁷ is Leu, Ace, or NIe;

A²⁸ is Ser, Ace, Act, Aib, Ape, or D- Arg;

A²⁹ is Arg, Ape, hArg, or Lys(N^ε-C(O)(CH₂)_m-CH₃); R¹ and R² each is, independently for each occurrence, selected from the group consisting of H, (Ci-C₃o)alkyl, (C₁-C₃₀)heteroalkyl, (C₂-C₃₀)acyl, (C₂-C₃₀)alkenyl, (C₂- C₃₀)alkynyl, aryl(Ci-C₃₀)alkyl, aryl(C₁-C₃o)acyl, substituted (d-C₃o)alkyl, substituted (Ci- C₃o)heteroalkyl, substituted (C₂-C₃o)acyl, substituted (C₂-C₃₀)alkenyl, substituted (C₂- C₃o)alkynyl, substituted aryl(Ci-C₃o)alkyl, substituted aryl(C₂-C₃o)acyl, 2-indolecarboxyl, 1- naphthoyl, 2-naphthoyl, and 4-biphenylcarboxyl; provided that when R¹ is (G₂-C₃o)acyl, aryl(Ci-C₃o)acyl, substituted (C₂-C₃₀)acyl, or substituted aryl(C ₁-C₃₀)acyl, R² is H, (C]-C₃₀)alkyl, (Ci-C₃₀)heteroalkyl, (C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl, aryl(Ci-C₃₀)alkyl, substituted (Ci-C₃₀)alkyl, substituted (C₁-C₃₀)heteroalkyl, substituted (C₂-C₃o)alkenyl, substituted (C₂-C₃₀)alkynyl, or substituted aryl(C₁-C₃₀)alkyl; R³ is -NH₂ or -OH; m is, independently for each occurrence, an integer from 1 to 40 inclusive; and n is, independently for each occurrence, an integer from 1 to 40 inclusive; provided that: (i) a compound of formula (I) contains at least one Ape, Apn, Cpa, Cpal, or Act;

(ii) a compound of formula (I) contains at least one Aib at position 2, 3, 4, 7, 8, 9, 15,

18, 19, 25, or 28; or

(iii) a compound of formula (I) contains Mop at position 10; or a pharmaceutically acceptable salt thereof. A more preferred embodiment of the invention provides a compound according to formula (I), wherein R¹ and R² each is, independently for each occurrence, selected from the group consisting of H, Ac, Ph-CH₂-C(O), (CH₃)₂CH-C(O), CH₃-(CH₂)_n-C(O), 4- chlorocinnamoyl, trans-cinnamoyl, p-tolylacetyl, 2-indolecarboxyl, 1-naphthoyl, 2-naphthoyl, 4-biphenylcarboxyl, 3-(p-tolyl)-propionyl, and trimethylacetyl. "Ace" in formula (I) stands for "1 -amino- l-cyclo(C₃-C₉)alkyl carboxylic acid" and includes, e.g., A3c which stands for "1 -amino- 1 -eye lopropanecarboxylic acid," A4c which stands for "1 -amino- 1-cyclobutanecarboxylic acid," A5c which stands for "1-amino-l- cyclopentanecarboxylic acid," and A6c which stands for "1 -amino- 1-cyclohexanecarboxylic acid." A subset of the compounds covered by the above formula (I) are those in which A² is an achiral amino acid such as, but not limited to, Ape, Aib, Ace, and Act.

In another subset of the compounds covered by formula (I) are those in which A² is a D-amino acid such as, but not limited to, D-Arg, D-Orn, D-Dab, D-Dap, D-VaI, D-Leu, D- Phe, D-Tφ, D-Tyr, D-Ser, D-Thr, D-GIu, D- Asp, and D-AIa. A preferred compound of formula (I) is where said compound is:

Example 1 : [Ac-Tyr¹, D-Arg², NIe²⁷, Aib²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 2)

Example 2: [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 3)

Example 3: [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c²⁶, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 4)

Example 4: [Ac-Tyr¹, D-Arg², A6c²⁶, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ED NO: 5) Example 5: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib²⁵, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 6)

Example 6: [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c²³, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 7)

Example 7: [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c²², NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 8) Example 8: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib¹⁹, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 9) Example 9: [Ph-CH₂-C(O)-TyT¹, D-Arg², NIe²⁷, Aib²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 10) Example 10: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib¹⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 11) Example 11: [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c¹⁷, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 12) Example 12: [Ph-CH₂-C(O)-TyT¹, D-Arg², A5c¹³, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 13) Example 13: [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 14) Example 14: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 15) Example 15: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib³, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 16) Example 16: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 17) Example 17: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁹, Nle²⁷JhGHRH(l-29)NH₂; (SEQ ID NO: 18) Example 18: [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c¹⁴, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 19) Example 19: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 20) Example 20: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁷, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 21)

Example 21: [Ph-CH₂-C(O)-TyT¹, D-Arg², Cpa⁶, Amp⁹, Mop¹⁰, Abu¹⁵, A6c²³, NIe²⁷, D-Arg²⁸, hArg²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 22)

Example 22: [Ph-CH₂-C(O)-TyT¹, D-Arg²'²⁸, Cpal⁶, hArg⁹'²⁹, Amp¹⁰, Abu¹⁵, NIe²⁷J hGHRH(l-29)NH₂; (SEQ ID NO: 23)

Example 23: [D-Arg^2>28, Cpal⁶, hArg⁹'²⁹, Amp¹⁰, Abu¹⁵, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 24) Example 24: [Ac-Tyr¹, D-Arg², Aib⁴'²⁵"²⁸, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 25)

Example 25: [Ac-Tyr¹, D-Arg², Aib³'²⁸, Brp⁶, Abu¹⁵, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 26)

Example 26: [Ac-Tyr¹, D-Arg², Aib⁴'²⁸, Brp⁶, Abu¹⁵, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 27) Example 27: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Brp⁶, Abu¹⁵, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 28)

Example 28: [Ac-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 29) Example 29: [Ac-Tyr¹, D-Arg², Aib⁴, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 30)

Example 30: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Cpa⁶, Abu¹⁵, A6c²³, NIe²⁷J hGHRH(l-29)NH₂; (SEQ ID NO: 31)

Example 31: [Ac-Tyr¹, D-Arg², Aib⁴'²⁸, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 32)

Example 32: [D-Arg², Aib⁴'²⁸, Cpa⁶, Leu²⁷JhGHRH(l-29)NH₂; (SEQ ID NO: 33)

Example 33: [Ac-Tyr¹, D-Arg², Aib⁴, Leu²⁷, ApC²⁹JhGHRH(I -29)NH₂; (SEQ ID NO: 34)

Example 34: [Ac-Tyr¹, D-Arg², β-Ala¹⁵, Aib⁴-²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 35) Example 35: [Ac-Tyr¹ , D-Arg², Aib⁴'²⁸, Cpa⁶, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 36)

Example 36: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, Cpa⁶, Abu¹⁵, NIe²⁷, D-Arg²⁸, hArg²⁹J hGHRH(l-29)NH₂; (SEQ ID NO: 37) Example 37: [Ph-CH₂-C(O)-TyT¹, D-Arg², Cpa⁶, hArg⁹, Mop¹⁰, Abu¹⁵, NIe²⁷, D-Arg²⁸, hArg²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 38)

Example 38: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 39) Example 39: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷, Act²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 40)

Example 40: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷, A5c²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 41)

Example 41 : [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Amp¹⁰, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 42)

Example 42: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Cpal⁶, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 43)

Example 43: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, β-Ala¹⁵, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 44) Example 44: [Ph-CH₂-C(O)-TyT¹, D-Lys², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 45)

Example 45: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Ape¹¹, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 46)

Example 46: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Ape¹², Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 47)

Example 47: [CH₃-(CH₂) _I2-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 48)

Example 48: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷, Lys(N^ε-tetradecanoyl)²⁹] hGHRH(l-29)NH₂; (SEQ ID NO: 49) Example 49: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Lys(N^ε-tetradecanoyl)²¹, NIe²⁷] hGHRH(l-29)NH₂; (SEQ ID NO: 50)

Example 50: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Lys(N^ε-tetradecanoyl)¹², NIe²⁷] hGHRH(l-29)NH₂; (SEQ ID NO: 51)

Example 51: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Lys(N^ε-tetradecanoyl)^H, Arg^12>21, NIe²⁷] hGHRH(l-29)NH₂; (SEQ ID NO: 52)

Example 52: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Apn¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 53)

Example 53: [Ph-CH₂-C(O)-TyT¹, Ape², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 54)

Example 54: [Ac-Tyr¹, Ape², Aib⁴"²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 55) Example 55: [Ph-CH₂-C(O)-TyT¹, Ape², Aib²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 56)

Example 56: [Ac-Tyr¹, Ape², Aib²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 57)

Example 57: [(CHj)₂CH-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(-l-29)NH₂; (SEQ ID NO: 58)

Example 58: [CH₃-(CH₂)Z-C(O)-TyT¹, D-Arg², Aib⁴"²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 59) Example 59: [4-chlorocinnamoyl-Tyr¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 60)

Example 60: [trans-cinnamoyl-Tyr¹, D-Arg², Aib⁴-²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 61) Example 61 : [p-tolylacetyl-Tyr¹ , D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH( 1 -29)NH₂; (SEQ ID NO: 62)

Example 62: [2-indolecarboxyl-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 63)

Example 63: [2-naphthoyl-Tyr¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 64)

Example 64: [1-naphthoyl-Tyr¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 65)

Example 65: [4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 66) Example 66: ^-(p-tolyφ-propionyl-Tyr¹, D-Arg², Aib⁴"²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 67)

Example 67: [trimethylacetyl-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 68)

Example 68: [Ph-CH₂-C(O)-TyT¹, Aib², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 69) Example 69: [Ph-CH₂-C(O)-TyT¹, D-Orn², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 70)

Example 70: [Ph-CH₂-C(O)-TyT¹, D-Dab², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 71)

Example 71: [Ph-CH₂-C(O)-TyT¹, D-Dap², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 72)

Example 72: [Ph-CH₂-C(O)-TyT¹, D-VaI², Aib⁴"²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 73)

Example 73: [Ph-CH₂-C(O)-TyT¹, D-Leu², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 74) Example 74: [Ph-CH₂-C(O)-TyT¹, D-Phe², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 75)

Example 75: [Ph-CH₂-C(O)-TyT¹, D-Trp², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 76)

Example 76: [Ph-CH₂-C(O)-TyT¹, D-Tyr², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 77)

Example 77: [Ph-CH₂-C(O)-TyT¹, D-Ser², Aib⁴'²⁸, NIe²⁷J hGHRH(l-29)NH₂; (SEQ ID NO: 78)

Example 78 f [Ph-CH₂-C(O)-TyT¹, D-Thr², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 79) Example 79: [Ph-CH₂-C(O)-TyT¹, D-GIu², Aib⁴"²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 80) Example 80: [Ph-CH₂-C(O)-TyT¹, D- Asp², Aib⁴"²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 81)

Example 81 : [Ph-CH₂-C(O)-TyT¹, D-AIa², Aib⁴-²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 82) Example 82: [CH₃-(CH₂)₁₀-C(O)-Tyr¹, D-Arg², Aib⁴"²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 83)

Example 83: [CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg², Aib⁴'²⁸,Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 84)

Example 84: [CH₃-(CH₂)₆-C(O)-Tyr', D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 85)

Example 85: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 86)

Example 86: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 87) Example 87: [CH₃-(CH₂)_J2-C(O)-TyT¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁸]hGHRH(l -29)NH₂; (SEQ ID NO: 88)

Example 88: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 89)

Example 89: [CH₃-(CH₂)_{! 2}-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 90)

Example 90: [CH₃-(CH₂)₄-C(O)-Tyr¹, D-Arg², Aib⁴"²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 91)

Example 91: [CH₃-(CH₂)₁₂-C(O)-Tyτ¹, Aib²'⁴"²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 92)

Example 92: [CH₃-(CH₂)_J2-C(O)-TyT¹, D-VaI², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 93)

Example 93: [CH₃-(CH₂)_K1-C(O)-TyT¹, Aib²'⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 94)

Example 94: [CH₃-(CH₂)₆-C(O)-Tyr\ D-VaI², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 95)

Example 95: [CH₃-(CH₂)₁₀-C(O)-Tyr¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 96)

Example 96: [CH₃-(CH₂)_O-C(O)-TyT¹, D-Arg², β-Ala¹⁵, Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 97)

Example 97: [CH₃-(CH₂)I₀-C(O)-TyT¹, D-VaI², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 98) Example 98: [CH₃-(CH₂)_I2-C(O)-TyT¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 99)

Example 99: [CH₃-(CH₂)₆-C(O)-Tyr\ D-Arg², Aib⁴, Leu²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 100)^~

Example 100: [CH₃-(CH₂)_O-C(O)-TyT¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 101) Example 101: [CH₃-(CH₂)₁₂-C(O)-Tyr¹, D-Arg², β-Ala¹⁵, Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 102)

Example 102: [Ph-CH₂-C(O)-HiS¹, D-Arg²'²⁸, Cpa⁶, Arg⁹, Abu¹⁵, NIe²⁷, hArg²⁹] hGHRH(l-29)NH₂; (SEQ ID NO: 103) Example 103: [4-biphenylcarboxyl-Tyr¹, D-VaI², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 104)

Example 104: [4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴, NIe²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 105)

Example 105: [4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴'²⁸, β-Ala¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 106)

Example 106: [4-biphenylcarboxyl-Tyr¹, Aib²'^4>28, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 107)

Example 107: [4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 108) Example 108: [4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 109)

Example 109: [4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴, NIe²⁷, Apc²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 110)

Example 110: [H-Tyr¹, D-Arg², A6c²⁶, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 111) Example 111: [H-Tyr¹, D-Arg², Aib²⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 112)

Example 112: [H-Tyr¹, D-Arg², A6c²³, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 113)

Example 113: [CH₃-(CH₂)_S-C(O)-TyT¹, Aib²'⁴'²⁸, Cpa⁶, Abu¹⁵, A6c²³, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 114)

Example 114: [CH₃-(CH₂)_S-C(O)-TyT¹, Aib²'⁴"²⁸, Abu¹⁵, A6c²³, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 115)

Example 115: [CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Cpa⁶, Abu¹⁵, A6c²³, NIe²⁷] hGHRH(l-29)NH₂; (SEQ ID NO: 116)

Example 116: [CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Abu¹⁵, A6c²³, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 117) Example 117: [CH₃-(CH₂)_S-C(O)-TyT¹, D-VaI², Aib⁴'²⁸, Cpa⁶, Abu¹⁵, A6c²³, NIe²⁷] hGHRH(l-29)NH₂; (SEQ ID NO: 118)

Example 118: [CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Abu¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 119)

Example 119: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴"²⁸, Cpa⁶, Abu¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 120)

Example 120: [CH₃-(CH₂)S-C(O)-TyT¹, D-Arg²'²⁸, Aib⁴, Cpa⁶, Abu¹⁵, NIe²⁷, hArg²⁹] hGHRH(l-2?)NH₂; (SEQ ID NO:_.121)

Example 121: [D-Arg², Aib⁴'²⁸, des-Phe⁶, Abu¹⁵, A6c²³, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 122) Example 122: [4-biphenylcarboxyl-Tyr¹, Ape², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; or (SEQ ID NO: 123) Example 123: [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Cpa⁶, His¹¹'²⁰, Abu¹⁵, NIe²⁷] hGHRH(l-29)NH₂; (SEQ ID NO: 125) or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a plot of tumor volumes in athymic mice bearing s.c. transplanted MX-I human mammary carcinoma cells (10 million cells injected per animal) during treatment with Example No. 118 (SEQ ID NO: 119) administered subcutaneously at doses of 0.5 and 1.0 mg/kg. The vehicle used was saline. Once daily treatment was started when the tumors measured approximately 74 mm³ and lasted for 3 weeks.

Figure 2 is a plot of tumor volumes in athymic mice bearing s.c. transplanted NCI- H69 human small cell lung cancer (SCLC) cells (8 million cells with equal volume Matrigel injected per animal) during treatment with Example No. 30 (SEQ ID NO: 31) administered intravenously at a dose of 50 mg/kg. This was also combined with cisplatin at a dose of 1 mg/kg (below the MTD) which is a standard chemotherapy used for SCLC to look for additivity or synergism. The vehicle used was saline. Once daily treatment every other day for 7 doses was started when tumors measured approximately 75 mm³ for Example No. 30 (SEQ ID NO: 31), while once daily cisplatin treatment was started when the tumors measured approximately 75 mm³ and lasted for 5 days. Figures 3 and 4 are plots of tumor volumes in athymic mice bearing s.c. transplanted

PC-3 human prostate cells (5 million cells with equal volume Matrigel injected per animal) during treatment with Example No. 30 (SEQ ID NO: 31) and Example No. 118 (SEQ ID NO: 119), respectively, administered subcutaneously at doses of 1 and 0.5 mg/kg. The vehicle used was saline. Once daily treatment every day for 21 doses was started when tumors measured approximately 90 mm³.

DETAILED DESCRIPTION OF THE INVENTION

Certain amino acids present in compounds of the invention can be and are represented herein as follows: Abu: α-aminobutyric acid

Ac: acetyl Act: 4-amino-4-carboxytetrahydropyran, i.e.,

Aib: α-aminoisobutyric acid β-Ala: beta-alanine

Amp: 4-amino-phenylalanine

Ape: amino piperidinylcarboxylic acid, i.e.,

Apn: aminopentanoic acid, i.e.,

hArg: homoarginine

4-biphenylcarboxyl :

Bφ: 4-bromo-phenylanaline

4-chlorocinnamoyl :

Cpa: 4-chloro-phenylalanine

^H2^N\^ ^{^}-OH

Cpal: β-cyclopropyl-alanine, i.e., Dab: 2,4-diaminobutyric acid Dap: 2,3-diaminopropionic acid

2-indolecarboxyl:

Mop: 4-methoxy-phenylanaline

1-naphthoyl:

2-naphthoyl:

NIe: norleucine

Orn: ornithine

Ph: phenyl

p-tolylacetyl:

3-(p-tolyl)-propionyl:

trans-cinnamoyl :

trimethylacetyl:

Certain other abbreviations used herein are defined as follows:

Boc: tert-butyloxycarbonyl

DCM: dichloromethane DIEA: diisopropylethyl amine

DMF dimethylformamide

Fmoc: Fluorenylmethyloxycarbonyl

HBTU: 2-( 1 H-benzotriazole- 1 -yl)- 1 , 1 ,3 ,3-tetramethyluronium hexafluorophosphate

HOBt: 1-hydroxy-benzotriazole NMP: N-methylpyrrolidone

Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl tBu: tert-butyl

TIS: triisopropylsilane

Trt: trityl TFA: trifluoro acetic acid

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.

A peptide of this invention is also denoted herein by another format, e.g., [D- Arg²]hGHRH(l-29)NH₂ (SEQ ID NO: 124), with the substituted amino acid(s) from the natural sequence placed between the first set of parentheses, e.g., D-Arg² for Ala² in hGHRH(l-29)NH₂ (SEQ ID NO: 1). The numbers between the second set of parentheses refer to the number of amino acids present in the peptide, e.g. , hGHRH(l -29)NH₂ (SEQ ID NO: 1), refers to amino acids 1 through 29 of the peptide sequence for human GHRH.

Examples are provided below to further illustrate different features of the present invention. The examples also illustrate useful methodology for practicing the invention. These examples do not limit the claimed invention. Synthesis

The compounds of the invention can be prepared using the techniques disclosed in the examples herein as well as techniques that are well known in the art. For example, a polypeptide region of a GHRH analogue can be chemically or biochemically synthesized and modified. Examples of techniques for biochemical synthesis involving the introduction of a nucleic acid into a cell and expression of nucleic acids are provided in Ausubel, Current Protocols in Molecular Biology, John Wiley (1987-1998); and Sambrook, et ah, in Molecular Cloning, A Laboratory Manual, 2^nd Edition, Cold Spring Harbor Laboratory Press (1989). Techniques for chemical synthesis of polypeptides are also well known in the art. See, e.g., Vincent, Peptide and Protein Drug Delivery, New York, N. Y., Dekker (1990). For example, the peptides of this invention can be prepared by standard solid phase peptide synthesis. See, e.g., Stewart, J.M., et al, Solid Phase Synthesis, Pierce Chemical Co., 2d ed. (1984).

A. Synthesis of Example 118. TCH₂-(CH₇WC(OVTVr¹. D-Arg². Aib⁴'²⁸. Abu¹⁵.

NIe²⁷IhGHRH(I -29)NH₂ (SEQ ID NO: 119)

The title peptide was synthesized on an Aapptec Apex 393 synthesizer using Fmoc chemistry. A Rink amide-4-methylbenzylhydrylamine (MBHA) resin (Novabiochem, San Diego, CA, U.S.A.) with substitution of 0.69 mmol/g was used. The Fmoc amino acids (Novabiochem, San Diego, CA, U.S.A.) used were: Fmoc-Arg(Pbf)-OH, Fmoc-D-Arg(Pbf)- OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Aib-OH, Fmoc-Gln(Trt)-OH, Fmoc- He-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Nle-OH, Fmoc-Phe-OH, Fmoc-Ser(tBu)- OH, Fmoc-Thr(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc- VaI-OH, and decanoic acid (Aldrich, 99.5%). The synthesis was carried out on a 0.304 mmol scale. The Fmoc groups were removed by treatment with 25% piperidine in N-methylpyrrolidone (NMP) for 5 minutes followed by 25 minutes. In each coupling step, the Fmoc amino acid (3.0 eq., 0.912 mmol), dissolved in a HOBt (1 eq.)/NMP solution was added followed by 1,3- diisopropylcarbodiiminde (3.0 eq. 0.91 mmole) in NMP. The Apex393 peptide synthesizer was programmed to perform the following reaction cycle: (1) washing with DMF, (2) removing Fmoc protecting group with 25% piperidine in DMF for 5 min followed by 25 minutes, (3) washing with DMF, and (4) double couple the Fmoc amino acid for 1 hour each. The following amino acids had a third_coupling with HBTU (3 eq.) and DIEA (5 eq.): Tyr¹, D-Arg², Asp³, Aib⁴-²⁸, He⁵, Phe⁶, Thr⁷, Asn⁸, Arg¹¹'²⁰-²⁹, VaI¹³, Ala¹⁹, Leu²²-²³, GIn²⁴, NIe²⁷, and decanoic acid. After the peptide chain was assembled the resin was washed completely by using NMP and DCM. At the end of the assembly of the peptide chain on the Apex393, the resin was washed with DMF and DCM. The title peptide was cleaved from the resin by treating with a mixture of TFA, H₂O and TIS (9.5 mL / 0.85 mL /0.8 mL) for 2 hours. The resin was filtered off and the filtrate was poured into 200 mL of ether. The precipitate was collected by centrifugation. This crude product was dissolved in a mixture of acetonitrile and water and purified on a reverse-phase preparative HPLC system with a Phenomenex Luna Ci₈ Prep column (21.2 x 250 mm). The column was eluted over 60 minutes using a linear gradient of 75% A : 25% B to 50% A : 50% B, where A was 0.1% TFA in water and B was 0.1% TFA in acetonitrile. The fractions were checked by analytical HPLC and those containing pure product were pooled and lyophilized to dryness to give 60.0mg (5.5%) of a white solid. Purity was assayed using HPLC and found to be approximately 99.0%. Electro-spray ionization mass spectrometry (ESI-MS) analysis gave the molecular weight at 3619.4 (in agreement with the calculated molecular weight of 3619.4).

B. Synthesis of Example 30. FPh-CH₂-CCOVT yr¹, D- Are². Aib⁴'²⁸. Cpa⁶. Abu¹⁵. A6c²³. NIe²⁷IhGHRHn -29WH₂ fSEO ID NO: 31)

The title peptide was synthesized on an Applied Biosystems model 433A peptide synthesizer (Foster City, CA, U.S.A.) using Fmoc chemistry. A Rink amide-4- methylbenzylhydrylamine (MBHA) resin (Novabiochem, San Diego, CA, U.S.A.) with substitution of 0.64 mmol/g was used. The Fmoc amino acids (AnaSpec, San Jose, CA, U.S.A.) used were: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-D-Arg(Pbf)-OH, Fmoc- Asn(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Aib-OH, Fmoc-Abu-OH, Fmoc-A6c-OH, Fmoc- Cρa-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Nle- OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Tyr(tBu)-OH, and Fmoc- VaI-OH. The synthesis was carried out on a 0.25 mmol scale. The Fmoc groups were removed by treatment with 20% piperidine in N-methylpyrrolidone (NMP) for 30 minutes. In each coupling step, the Fmoc amino acid (3 eq., 0.3 mmol) was first pre-activated in 2 mL solution of 0.45M 2-(l -H-benzotriazole- 1 -yl)- 1 , 1 ,2,3-tetramethyluronium hexafluorophosphate/1 - hydroxy-benzotriazole (HBTU/HOBt) in NMP. This activated amino acid ester, 1 mL of DIEA and 1 mL of NMP were added to the resin. The ABI 433A peptide synthesizer was programmed to perform the following reaction cycle: (1) washing with NMP, (2) removing Fmoc protecting group with 20% piperidine in NMP for 30 min, (3) washing with NMP, and (4) coupling with pre-activated Fmoc amino acid for 1 or 2 hours. The resin was coupled successively according to the sequence of the title peptide. After the peptide chain was assembled, the resin was washed completely by using NMP and DCM.

At the end of the assembly of the peptide chain on the 433 A, the peptide-resin was transferred to a reaction vessel on a shaker and the Fmoc was removed using 25% Pip/DMF for 30 min. The resin was washed with DMF and DCM. The resin was reacted with phenacyl chloride (10 eq., 2.5mmole) and DIEA (12 eq., 3mmole) in DCM for 30 minutes. The resin was washed with DCM. The title peptide was cleaved from the resin by treating with a mixture of TFA, H₂O and TIS (9.5 mL / 0.85 mL /0.8 mL) for 2 hours. The resin was filtered off and the filtrate was poured into 200 mL of ether. The precipitate was collected by centrifugation. This crude product was dissolved in a mixture of acetonitrile and water and purified on a reverse-phase preparative HPLC system with a column (25 x 150 mm) of PLRP-S IOOA 8μm. The column was eluted over approximately 80 minutes using a linear gradient of 95% A : 5% B to 40% A : 60% B, where A was 0.1% TFA in water and B was 0.1% TFA in acetonitrile. The fractions were checked by analytical HPLC and those containing pure product were pooled and lyophilized to dryness to give 139.6 mg (15.4%) of a white solid. Purity was assayed using HPLC and found to be approximately 98.5%. Electro-spray ionization mass spectrometry (ESI-MS) analysis gave the molecular weight at 3629.2 (in agreement with the calculated molecular weight of 3629.7).

C. Synthesis of Example 34. r Ac-Tw¹. D-Arg². β-Ala¹⁵. Aib⁴-²⁸. NIe²⁷IhGHRH(I -29)NH? (SEQ ID NO: 35)

The title peptide was synthesized on an Applied Biosystems model 433A peptide synthesizer (Foster City, CA, U.S.A.) using Fmoc chemistry. A Rink amide-4- methylbenzylhydrylamine (MBHA) resin (Novabiochem, San Diego, CA, U.S.A.) with substitution of 0.64 mmol/g was used. The Fmoc amino acids (AnaSpec, San Jose, CA, U.S.A.) used were: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-D-Arg(Pbf)-OH, Fmoc- Asn(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Aib-OH, Fmoc-β-Ala-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Nle-OH, Fmoc-Phe-OH, Fmoc- Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Tyr(tBu)-OH, and Fmoc- VaI-OH. The synthesis was carried out on a 0.25 mmol scale. The Fmoc groups were removed by treatment with 20% piperidine in N-methylpyrrolidone (NMP) for 30 min. In each coupling step, the Fmoc amino acid (3 eq., 0.3 mmol) was first pre-activated in 2 mL solution of 0.45M 2-(1-H- benzotriazole- 1 -yl)- 1 , 1 ,2,3-tetramethyluronium hexafiuorophosphate/1 -hydroxy- benzotriazole (HBTU/HOBt) in NMP. This activated amino acid ester, 1 mL of DIEA and 1 mL of NMP were added to the resin. The ABI 433 A peptide synthesizer was programmed to perform the following reaction cycle: (1) washing with NMP, (2) removing Fmoc protecting group with 20% piperidine in NMP for 30 minutes, (3) washing with NMP, and (4) coupling with pre-activated Fmoc amino acid for 1 or 2 hours. The resin was coupled successively according to the sequence of the title peptide. After the last amino acid was coupled the Fmoc was deblocked and the peptide was capped using 5% acetic anhydride (Aldrich, 99%) and 2.5% DIEA. After the peptide chain was assembled the resin was washed completely by using NMP and DCM.

At the end of the assembly of the peptide chain on the 433 A the resin was washed with DMF and DCM. The title peptide was cleaved from the resin by treating with a mixture of TFA, H₂O and TIS (9.5 mL / 0.85 mL /0.8 mL) for 2h. The resin was filtered off and the filtrate was poured into 200 mL of ether. The precipitate was collected by centrifugation. This crude product was dissolved in a mixture of acetonitrile and water and purified on a reverse-phase preparative HPLC system with a column (25 x 150 mm) of PLRP-S IOOA 8μm. The column was eluted over approximately 80 minutes using a linear gradient of 95% A : 5% B to 40% A : 60% B, where A was 0.1% TFA in water and B was 0.1% TFA in acetonitrile. The fractions were checked by analytical HPLC and those containing pure product were pooled and lyophilized to dryness to give 10.8 mg (1.2%) of a white solid. Purity was assayed using HPLC and found to be approximately 97.2%. Electro-spray ionization mass spectrometry (ESI-MS) analysis gave the molecular weight at 3493.3 (in agreement with the calculated molecular weight of 3493.2).

D.

hGHRHd -29WH₂ (SEQ ID NO: 102)

The title peptide was synthesized on an Aapptec Apex 393 synthesizer using Fmoc chemistry. A Rink amide-4-methylbenzylhydrylamine (MBHA) resin (Novabiochem, San Diego, CA, U.S.A.) with substitution of 0.69 mmol/g was used. The Fmoc amino acids (Novabiochem, San Diego, CA, U.S.A.) used were: Fmoc-Arg(Pbf)-OH, Fmoc-D-Arg(Pbf)- OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Aib-OH, Fmoc-β-Ala-OH, Fmoc- Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Nle-OH, Fmoc-Phe- OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc- VaI-OH, and myristic acid (Aldrich, 99.5%). The synthesis was carried out on a 0.304 mmol scale. The Fmoc groups were removed by treatment with 25% piperidine in N-methylpyrrolidone (NMP) for 5 minutes followed by 25 minutes. In each coupling step, the Fmoc amino acid (3.6 eq., 1.09 mmol), dissolved in a HOBt(I eq.)/NMP solution was added followed by 1,3- Diisopropylcarbodiiminde (3.6 eq., 1.09 mmole) in NMP. The Apex393 peptide synthesizer was programmed to perform the following reaction cycle: (1) washing with DMF, (2) removing Fmoc protecting group with 25% piperidine in DMF for 5 minutes followed by 25 minutes, (3) washing with DMF, and (4) double couple the Fmoc amino acid for 1 hour each. The following amino acids had a third coupling with HBTU (3 eq.) and DIEA (5 eq.): D- Arg², Arg¹¹'²⁰'²⁹, Asp³, Aib⁴'²⁸, VaI¹³, Leu¹⁴, β-Ala¹⁵, GIn¹⁶"²⁴, NIe²⁷, and myristic acid. After the peptide chain was assembled, the resin was washed completely by using NMP and DCM.

At the end of the assembly of the peptide chain on the Apex393, the resin was washed with DMF and DCM. The title peptide was cleaved from the resin by treating with a mixture of TFA, H₂O and TIS (9.5 ml_ / 0.85 mL /0.8 mL) for 2 hours. The resin was filtered off and the filtrate was poured into 200 mL of ether. The precipitate was collected by centrifugation. This crude product was dissolved in a mixture of acetonitrile and water and purified on a reverse-phase preparative HPLC system with a Phenomenex Luna Ci₈ Prep column (21.2 x 250 mm). The column was eluted over 60 minutes using a linear gradient of 90% A : 10% B to 50% A : 50% B, where A was 0.1% TFA in water and B was 0.1% TFA in acetonitrile. The fractions were checked by analytical HPLC and those containing pure product were pooled and lyophilized to dryness to give 166.2mg (15.1%) of a white solid. Purity was assayed using HPLC and found to be approximately 99.0%. Electro-spray ionization mass spectrometry (ESI-MS) analysis gave the molecular weight at 3661.3 (in agreement with the calculated molecular weight of 3661.4).

E. Synthesis of Example 104. K-biphenylcarboxyl-Tyr¹. D- Are². Aib⁴. NIe²⁷. ApC²⁸I hGHRH(l-29')NH_? (SEQ ID NO: 105)

The title peptide was synthesized on an Aapptec Apex 393 synthesizer using Fmoc chemistry. A Rink amide-4-methylbenzylhydrylamine (MBHA) resin (Novabiochem, San Diego, CA, U.S.A.) with substitution of 0.69 mmol/g was used. The Fmoc amino acids (Novabiochem, San Diego, CA, U.S.A.) used were: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-D-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Aib-OH, Fmoc- Apc(Boc)-OH Fmoc-Gln(Trt)-OH, Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc- Lys(Boc)-OH, Fmoc-Nle-OH, Fmoc-Phe-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc- VaI-OH, and 4-biphenylcarboxylic Acid (Aldrich, 99.5%). The synthesis was carried out on a 0.304 mmol scale. The Fmoc groups were removed by treatment with 25% piperidine in N-methylpyrrolidone (NMP) for 5 minutes followed by 30 minutes. In each coupling step, the Fmoc amino acid (3.6 eq., 1.09 mmol), dissolved in a HOBt (1 eq.)/NMP solution was added followed by 1,3-Diisopropylcarbodiiminde (3.6 eq., 1.09 mmole) in NMP. The Apex393 peptide synthesizer was programmed to perform the following reaction cycle: (1) washing with DMF, (2) removing Fmoc protecting group with 25% piperidine in DMF for 5 minutes followed by 25 minutes, (3) washing with DMF, and (4) double couple the Fmoc amino acid for 1 hour each. The following amino acids had a third coupling with HBTU (3 eq.) and DIEA (5 eq.): Tyr¹'¹⁰, D-Arg², Arg¹¹'²⁰'²⁹, Asp³, Aib⁴, VaI¹³, GIy¹⁵, He⁵, Leu²²'²³, β-Asp⁸, GIn¹⁶'²⁴, NIe²⁷, Ser⁹, Ala¹⁶, Ape²⁸, and 4- biphenylcarbosylic acid. After the peptide chain was assembled, the resin was washed completely by using NMP and DCM. The resin was washed with DMF and DCM.

The title peptide was cleaved from the resin by treating with a mixture of TFA, H₂O and TIS (9.5 mL / 0.85 mL /0.8 mL) for 2 hours. The resin was filtered off and the filtrate was poured into 200 mL of ether. The precipitate was collected by centrifugation. This crude product was dissolved in a mixture of acetonitrile and water and purified on a reverse- phase preparative HPLC system with a Phenomenex Luna C₁₈ Prep column (21.2 x 250 mm). The column was eluted over 60 minutes using a linear gradient of 90% A : 10% B to 50% A : 50% B, where A was 0.1% TFA in water and B was 0.1% TFA in acetonitrile. The fractions were checked by analytical HPLC and those containing pure product were pooled and lyophilized to dryness to give 92.8mg (8.5%) of a white solid. Purity was assayed using HPLC and found to be approximately 99.0%. Electro-spray ionization mass spectrometry (ESI-MS) analysis gave the molecular weight at 3658.8 (in agreement with the calculated molecular weight of 3658.3).

F. Synthesis of Example 107. r4-biphenylcarboxyl-Tyr¹. D-Arg². Aib⁴. Leu²⁷. ApC²⁸IhGHRH(I -291NH₇ (SEQ ID NO: 108)

The title peptide was synthesized on an Aapptec Apex 393 synthesizer using Fmoc chemistry. A Rink amide-4-methylbenzylhydrylamine (MBHA) resin (Novabiochem, San Diego, CA, U.S.A.) with substitution of 0.69 mmol/g was used. The Fmoc amino acids (Novabiochem, San Diego, CA, U.S.A.) used were: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-D-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Aib-OH, Fmoc- ^' Apc(Boc)-OH,^"Fmoc-Gln(Trt)-OH, Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc- - Lys(Boc)-OH, Fmoc-Nle-OH, Fmoc-Phe-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc- VaI-OH, and 4-biphenylcarboxylic Acid (Aldrich, 99.5%). The synthesis was carried out on a 0.304 mmol scale. The Fmoc groups were removed by treatment with 25% piperidine in N-methylpyrrolidone (NMP) for 5 minutes followed by 30 minutes. In each coupling step, the Fmoc amino acid (3.6 eq., 1.09 mmol), dissolved in a HOBt (1 eq.)/NMP solution was added followed by 1,3-Diisopropylcarbodiiminde (3.6 eq., 1.09 mmole) in NMP. The Apex393 peptide synthesizer was programmed to perform the following reaction cycle: (1) washing with DMF, (2) removing Fmoc protecting group with 25% piperidine in DMF for 5 minutes followed by 25 minutes, (3) washing with DMF, and (4)double couple the Fmoc amino acid for 1 hour each. The following amino acids had a third coupling with HBTU (3 eq.) and DIEA (5 eq.): Tyr¹'¹⁰, D-Arg², Arg¹¹'²⁰'²⁹, Asp³, Aib⁴, VaI¹³, GIy¹⁵, He⁵, Leu²²'²³'²⁷, β-Asp⁸, GIn¹⁶'²⁴, Ser⁹, Ala¹⁶, Ape²⁸, and 4-biphenylcarbosylic acid. After the peptide chain was assembled the resin was washed completely by using NMP and DCM. The resin was washed with DMF and DCM.

The title peptide was cleaved from the resin by treating with a mixture of TFA, H₂O and TIS (9.5 mL / 0.85 mL / 0.8 mL) for 2 hours. The resin was filtered off and the filtrate was poured into 200 mL of ether. The precipitate was collected by centrifugation. This crude product was dissolved in a mixture of acetonitrile and water and purified on a reverse- phase preparative HPLC system with a Phenomenex Luna C₁₈ Prep column (21.2 x 250 mm). The column was eluted over 60 minutes using a linear gradient of 90% A : 10% B to 50% A : 50% B, where A was 0.1% TFA in water and B was 0.1% TFA in acetonitrile. The fractions were checked by analytical HPLC and those containing pure product were pooled and lyophilized to dryness to give 86.5 mg (7.9%) of a white solid. Purity was assayed using HPLC and found to be approximately 99.0%. Electro-spray ionization mass spectrometry (ESI-MS) analysis gave the molecular weight at 3658.6 (in agreement with the calculated molecular weight of 3658.3).

Other peptides of the invention can be prepared by a person of ordinary skill in the art using synthetic procedures analogous to those disclosed in the foregoing examples. Physical data for the compounds exemplified herein are given in Table 1.

TABLE l

Functional Assays

A. In Vitro GHRH Receptor Binding Assay

Human embryonic kidney (HEK-239) cells expressing the human GHRH receptor were obtained from Dr. Kelly Mayo (Northwestern University, Chicago, IL, U.S.A.), were grown in 10% DMEM (high glucose), containing 10% fetal calf serum and 0.40 mg/ml G418 (Gibco®). The incubation atmosphere consisted of 95% air / 5% CO₂ at 37 ⁰C. The nomenclature for the line expressing the human receptor is HPR9.

Membranes were prepared by homogenization of the HPR9 cells in 20 ml of ice-cold Buffer A with a Brinkman Polytron (setting 6, 15 sec). Buffer was added to obtain a final volume of 40 ml, and the homogenate was centrifuged in a Sorval SS-34 rotor at 39,000 g for 10 min at 4 ⁰C. The resulting supernatant was decanted, and the pellet was rehomogenized in ice-cold buffer A, diluted, and centrifuged as before. The final pellet was resuspended in Buffer B, and held on ice for the receptor binding assay.

For assay, aliquots (0.30 ml) were incubated with 0.10 ml (-75,000 cpm) [¹²⁵I]GRF(l-44) (-2200 Ci/mmol, New England Nuclear) in Buffer B, with or without 0.05 ml of the unlabeled competing peptides. After a 120 min incubation (23 ⁰C), the bound radioligand was separated from the free by rapid filtration through GF/C filters, previously soaked (2 hours) in 0.5% polyetheneimine and 0.1% BSA. The filters were then washed three times with 5-ml aliquots of ice-cold Buffer C. Specific binding was defined as the total [¹²⁵I]GRF(I -44) bound minus that bound in the presence of 1 μM unlabeled [D-AIa²] GRF(I - 29)-NH2. In vitro GHRH receptor binding data for the compounds exemplified herein are given in Table 2.

B. GHRH Antagonistic Bioassav

Human kidney 293 (293-HPR9) cells, stably expressing the human GRF receptor, were seeded into 24-well plates and cultured for 1-2 days. Subsequently, the culture media was removed, replaced with Hank's-buffered saline (HBSS) containing 0.5 mM IBMX, and pre-incubated for 30 minutes at 37 ⁰C. At the end of the pre-incubation period the GHRH antagonist peptides and GRF(I -29) (10 nM) were added and the cells were incubated for an additional 30 minutes. The incubation was terminated by the addition of 0.5 ml ice-cold absolute ethanol and aliquots were analyzed for cyclic AMP content using a New England Nuclear radioimmunoassay kit. GHRH antagonistic activity data for the compounds exemplified herein are given in Table 2.

C. Rat Plasma Half-Life (T \n) Assay GHRH peptide (50 μL 500 μg/mL) was added to 450 μL rat plasma, vertexed briefly and incubated at 37 ⁰C. 50 μL was removed at various times, like at 0, 1, 2, 3, 4, 8, 24, 32, 48, 56, 72, and 80 hours, acidified with 5 μL formic acid, mixed, added with 150 μL acetonitrile in a microcentrifuge tube, vertexed, and centrifuged for 10 minutes at 1OK rpm. The supernatant was transferred to an injection vial and analyzed by LC-MS. The LC-MS system consisted of a Finnigan Deca XP mass spectrometer with an ESI probe. Positive ion mode and full scan detection were used. HPLC separation was carried out on a Luna 3μ C8 (2), 3 x 50 mm column with a gradient from 100% A to 80% B in 10 minutes at a flow rate of 0.25 ml/min. Buffer A was 1% formic acid in water and buffer B was 1% formic acid in acetonitrile. Rat plasma half-life data for the compounds exemplified herein are given in Table 2.

TABLE 2

D. In Vivo Growth Assay

Figure 2 is a plot of tumor volumes in athymic mice bearing s.c. transplanted NCI- H69 human small cell lung cancer (SCLC) cells (8 million cells with equal volume Matrigel injected per animal) during treatment with Example No. 30 (SEQ ID NO: 31) administered intravenously at a dose of 50 mg/kg. This was also combined with cisplatin at a dose of 1 mg/kg (below the MTD) which is a standard chemotherapy used for SCLC to look for additivity or synergism. The vehicle used was saline. Once daily treatment every other day for 7 doses was started when tumors measured approximately 75 mm³ for Example No. 30 (SEQ ED NO: 31), while once daily cisplatin treatment was started when the tumors measured approximately 75 mm³ and lasted for 5 days. Figures 3 and 4 are plots of tumor volumes in athymic mice bearing s.c. transplanted PC-3 human prostate cells (5 million cells with equal volume Matrigel injected per animal) during treatment with Example No. 30 (SEQ ID NO: 31) and Example No. 118 (SEQ ID NO: 119), respectively, administered subcutaneously at doses of 1 and 0.5 mg/kg. The vehicle used was saline. Once daily treatment every day for 21 doses was started when tumors measured approximately 90 mm³.

Administration

GHRH analogues can be formulated and administered to a subject using the guidance provided herein along with techniques well known in the art. The preferred route of administration ensures that an effective amount of compound reaches the target. Guidelines for pharmaceutical administration in general are provided in, for example, Remington 's Pharmaceutical Sciences 18^th Edition, Ed. Gennaro, Mack Publishing (1990), and Modem Pharmaceutics 2^nd Edition, Eds. Banker and Rhodes, Marcel Dekker, Inc. (1990), both of which are hereby incorporated by reference herein. GHRH analogues can be prepared as acidic or basic salts. Pharmaceutically acceptable salts (in the form of water- or oil-soluble or dispersible products) include conventional non-toxic salts or the quaternary ammonium salts that are formed, e.g., from inorganic or organic acids or bases.

GHRH analogues can be administered using different routes including oral, nasal, by injection, transdermal, and transmucosally. Active ingredients to be administered orally as a suspension can be prepared according to techniques well known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants.

Administered by nasal aerosol or inhalation formulations may be prepared, for example, as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, employing fluorocarbons, and/or employing other solubilizing or dispersing agents.

GHRH analogues may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form. When administered by injection, the injectable solution or suspension may be formulated using suitable non-toxic, parenterally-acceptable diluents or solvents, such as Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

Suitable dosing regimens are preferably determined taking into account factors well known in the art including type of subject being dosed; age, weight, sex and medical condition of the subject; the route of administration; the renal and hepatic function of the subject; the desired effect; and the particular compound employed. Optimal precision in achieving concentrations of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug. The daily dose for a subject is expected to be between 0.01 and 1,000 mg per subject per day. The invention has been described in an illustrative manner, and it is to be understood that the terminology which has been used is intended to be in the nature of words of description rather than of limitation. Obviously, many modifications and variations of the present invention are possible in light of the above teachings. Therefore, it is to be understood that within the scope of the appended claims the invention may be practiced otherwise than as specifically described.

The patent and scientific literature referred to herein represents knowledge that is available to those with skill in the art. All patents, patent publications and other publications cited herein are hereby incorporated by reference in their entirety.

Claims

1. A compound according to formula (I):

(R¹R²)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-Aⁿ-A¹²-A¹³-A¹⁴-A¹⁵-Gln-A¹⁷-A¹⁸-A¹⁹-A²⁰- _A ²¹-A²²-A²³-Gln-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-R³

(I) wherein:

A¹ is Tyr or His; A² is Ape, Aib, Act, D-Arg, D-Orn, D-Dab, D-Dap, D-VaI, D-Leu, D-Phe, D-Trp, D-

Tyr, D-Ser, D-Thr, D-GIu, D- Asp, or D-AIa;

A³ is Asp or Aib;

A⁴ is Ala or Aib;

A⁵ is He or Ace; A⁶ is Phe, Brp, Cpa, Cpal, or des-Phe;

A⁷ is Thr or Aib;

A⁸ is Asn or Aib;

A⁹ is Ser, Aib, Amp, Arg, or hArg;

A¹⁰ is Tyr, Amp or Mop; A¹¹ is Arg, Ape, His, or Lys(N^ε-C(O)(CH₂)_m-CH₃);

A¹² is Lys, Ape, Arg, or Lys(N^ε-C(O)(CH₂)_m-CH₃);

A¹³ is VaI or Ace;

A¹⁴ is Leu or Ace;

A¹⁵ is GIy, Aib, Apn, Abu, or β-Ala; A¹⁷ is Leu or Ace;

A¹⁸ is Ser or Aib;

A¹⁹ is Ala or Aib;

A²⁰ is Arg or His;

A²¹ is Lys, Arg, or Lys(N^e-C(O)(CH₂)_m-CH₃); A²² is Leu or Ace;

A²³ is Leu or Ace;

A²⁵ is Asp or Aib;

A²⁶ is He or Ace;

A²⁷ is Leu, Ace, or NIe; A is Ser, Ace, Act, Aib, Ape, or D-Arg;

A²⁹ is Arg, Ape, hArg, or Lys(N^ε-C(O)(CH₂)_m-CH₃); R¹ and R² each is, independently for each occurrence, selected from the group consisting of H, (C]-C₃₀)alkyl, (C₁-C₃₀)heteroalkyl, (C₂-C₃₀)acyl, (C₂-C₃₀)alkenyl, (C₂- C₃₀)alkynyl, aryl(Ci-C₃o)alkyl, aryl(CrC₃₀)acyl, substituted (d-C₃o)alkyl, substituted (C_r C₃o)heteroalkyl, substituted (C₂-C₃₀)acyl, substituted (C₂-C₃₀)alkenyl, substituted (C₂- C₃₀)alkynyl, substituted aryl(C₁-C₃₀)alkyl, substituted aryl(C₂-C₃o)acyl, 2-indolecarboxyl, 1- naphthoyl, 2-naphthoyl, and 4-biphenylcarboxyl; provided that when R¹ is (C₂-C₃₀)acyl, aryl(CrC₃o)acyl, substituted (C₂-C₃₀)acyl, or substituted aryl(CrC₃₀)acyl, R² is H, (C₁-C₃₀)alkyl, (C_rC₃₀)heteroalkyl, (C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl, aryl(C₁-C₃₀)alkyl, substituted (C₁-C₃₀)alkyl, substituted (CrC₃o)heteroalkyl, substituted (C₂-C₃₀)alkenyl, substituted (C₂-C₃₀)alkynyl, or substituted aryl(Ci-C₃o)alkyl; R³ is -NH₂ or -OH; m is, independently for each occurrence, an integer from 1 to 40 inclusive; and n is, independently for each occurrence, an integer from 1 to 40 inclusive; provided that: (i) a compound of formula (I) contains at least one Ape, Apn, Cpa, Cpal, or Act;

18, 19, 25, or 28; or

(iii) a compound of formula (I) contains Mop at position 10; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein R¹ and R² each is, independently for each occurrence, selected from the group consisting of H, Ac, Ph-CH₂-C(O), (CH₃)₂CH-C(O), CH₃-(CH₂)_n-C(O), 4-chlorocinnamoyl, trans-cinnamoyl, p-tolylacetyl, 2-indolecarboxyl, 1- naphthoyl, 2-naphthoyl, 4-biphenylcarboxyl, 3-(p-tolyl)-propionyl, and trimethylacetyl.

3. A compound according to claim 2, wherein said compound is: [Ac-Tyr¹, D-Arg², NIe²⁷, Aib²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 2) [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 3) [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c²⁶, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 4) [Ac-Tyr¹, D-Arg², A6c²⁶, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 5)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib²⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO:- 6) [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c²³, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 7) [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c²², Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 8) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib¹⁹, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 9) [Ph-CH₂-C(O)-TyT¹, D-Arg², NIe²⁷, Aib²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 10) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib¹⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 11) [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c¹⁷, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 12) [Ph-CH₂-C(O)-TyT¹, D-Arg², A5c¹³, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 13) [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c⁵, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 14) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 15) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib³, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 16) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 17) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁹, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 18) [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c¹⁴, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 19) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 20) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁷, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 21)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Cpa⁶, Amp⁹, Mop¹⁰, Abu¹⁵, A6c²³, NIe²⁷, D-Arg²⁸, hArg²⁹J hGHRH(l-29)NH₂; (SEQ ID NO: 22) [Ph-CH₂-C(O)-TyT¹, D-Arg²'²⁸, Cpal⁶, hArg⁹'²⁹, Amp¹⁰, Abu¹⁵, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 23)

[D-Arg²'²⁸, Cpal⁶, hArg⁹'²⁹, Amp¹⁰, Abu¹⁵, NIe²⁷J hGHRH(l-29)NH₂; (SEQ ID NO: 24) [Ac-Tyr¹, D-Arg², Aib⁴'²⁵'²⁸, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 25) [Ac-Tyr¹, D-Arg², Aib³'²⁸, Brp⁶, Abu¹⁵, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 26) [Ac-Tyr¹, D-Arg², Aib⁴'²⁸, Brp⁶, Abu¹⁵, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 27)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Brp⁶, Abu¹⁵, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 28)

[Ac-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 29) [Ac-Tyr¹, D-Arg², Aib⁴, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 30) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Cpa⁶, Abu¹⁵, A6c²³, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 31)

[Ac-Tyr¹, D-Arg², Aib⁴'²⁸, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 32) [D-Arg², Aib⁴'²⁸, Cpa⁶, LeU²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 33) [Ac-Tyr¹, D-Arg², Aib⁴, Leu²⁷, ApC²⁹JhGHRH(I -29)NH₂; (SEQ ID NO: 34) [Ac-Tyr¹, D-Arg², β-Ala¹⁵, Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 35) [Ac-Tyr¹, D-Arg², Aib⁴'²⁸, Cpa⁶, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 36)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, Cpa⁶, Abu¹⁵, NIe²⁷, D-Arg²⁸, hArg²⁹JhGHRH(l-29)NH₂; (SEQ ID NO: 37)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Cpa⁶,^" hArg⁹, Mop¹⁰, Abu¹⁵, NIe²⁷, D-Arg²⁸, hArg²⁹] hGHRH(l- 29)NH₂; (SEQ ID NO: 38)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, Leu²⁷, ApC²⁸JhGHRH(I -29)NH₂; (SEQ ID NO: 39) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷, Act²⁸JhGHRH(l-29)NH₂; (SEQ ID NO: 40) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷, A5c²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 41) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Amp¹⁰, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 42) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Cpal⁶, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 43) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, β-Ala¹⁵, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 44) [Ph-CH₂-C(O)-TyT¹, D-Lys², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 45)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Ape¹¹, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 46) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Ape¹², Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 47) [CH₃-(CH₂)_J2-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 48)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷, Lys(N^ε-tetradecanoyl)²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 49)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Lys(N^ε-tetradecanoyl)²¹, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 50)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Lys(N^ε-tetradecanoyl)¹², Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 51) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Lys(N^ε-tetradecanoyl)^π, Arg¹²'²¹, NIe²⁷JhGHRH(I- 29)NH₂; (SEQ ID NO: 52)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Apn¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 53) [Ph-CH₂-C(O)-TyT¹, Ape², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 54) [Ac-Tyr¹, Ape², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 55) [Ph-CH₂-C(O)-TyT¹, Ape², Aib²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 56) [Ac-Tyr¹, Ape², Aib²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 57) [(CH₃^CH-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 58) [CH₃-(CH₂^-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 59) [4-chlorocinnamoyl-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 60) [trans-cinnamoyl-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷J hGHRH(l-29)NH₂; (SEQ ID NO: 61) [p-tolylacetyl-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 62) [2-indolecarboxyl-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 63) [2-naphthoyl-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 64) [1-naphthoyl-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 65) [4-biphenylcarboxyl-Tyr¹ , D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 66) ^-(p-tolyO-propionyl-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 67) [trimethylacetyl-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 68) [Ph-CH₂-C(O)-TyT¹, Aib², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 69) [Ph-CH₂-C(O)-TyT¹, D-Orn², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 70) [Ph-CH₂-C(O)-TyT¹, D-Dab², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 71) [Ph-CH₂-C(O)-TyT¹, D-Dap², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 72) [Ph-CH₂-C(O)-TyT¹, D-VaI², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 73) [Ph-CH₂-C(O)-TyT¹, D-Leu², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 74) [Ph-CH₂-C(O)-TyT¹, D-Phe², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 75) [Ph-CH₂-C(O)-TyT¹, D-Trp², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 76) [Ph-CH₂-C(O)-TyT¹, D-Tyr², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 77) [Ph-CH₂-C(O)-TyT¹, D-Ser², Aib⁴"²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 78) [Ph-CH₂-C(O)-TyT¹, D-Thr², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 79) [Ph-CH₂-C(O)-TyT¹, D-GIu², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 80) [Ph-CH₂-C(O)-TyT¹, D-Asp², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 81) [Ph-CH₂-C(O)-TyT¹, D-AIa², Aib⁴"²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 82)

[CH₃-(CH₂)_I0-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 83) [CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg², Aib⁴'²⁸,Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 84) [CH₃-(CH₂)_O-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 85) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 86) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 87)

[CH₃-(CH₂)_I2-C(O)-TyT¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 88) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 89) [CH₃-(CH₂)_I2-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 90) [CH₃-(CH₂VC(O)-TyT¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 91) [CH₃-(CHz)₁₂-C(O)-TyT¹, Aib²'⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 92)

[CH₃-(CH₂)₁₂-C(O)-Tyr¹, D-VaI², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 93) [CH₃-(CHz)₁₀-C(O)-TyT¹, Aib²'⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 94) [CH₃-(CH₂)₆-C(O)-Tyr¹, D-VaI², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 95) [CH₃-(CH₂)_J0-C(O)-TyT¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 96) [CH₃-(CH₂)₆-C(O)-Tyr¹, D-Arg², β-Ala¹⁵, Aib⁴-²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 97)

[CH₃-(CH₂)_I0-C(O)-TyT¹, D-VaI², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 98) [CH₃-(CH₂)_J2-C(O)-TyT¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 99) [CH₃-(CH₂)_O-C(O)-TyT¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 100) [CH₃-(CH₂)_O-C(O)-TyT¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 101)

[CH₃-(CH₂)_I2-C(O)-TyT¹, D-Arg², β-Ala¹⁵, Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 102)

[Ph-CH₂-C(O)-HiS¹, D-Arg²'²⁸, Cpa⁶, Arg⁹, Abu¹⁵, NIe²⁷, hArg²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 103) [4-biphenylcarboxyl-Tyr¹, D-VaI², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 104)

[4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴, NIe²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 105) [4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴'²⁸, β-Ala¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 106)

[4-biphenylcarboxyl-Tyr¹, Aib²'⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 107)

[4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 108)

[4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 109)

[4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴, NIe²⁷, Apc²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 110) [H-Tyr¹, D-Arg², A6c²⁶, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ED NO: 111) [H-Tyr¹, D-Arg², Aib²⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 112) [H-Tyr¹, D-Arg², A6c²³, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 113)

[CH₃-(CH₂)_S-C(O)-TyT¹, Aib^2>4'²⁸, Cpa⁶, Abu¹⁵, A6c²³, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 114)

[CH₃-(CH₂)_S-C(O)-TyT¹, Aib²'⁴'²⁸, Abu¹⁵, A6c²³, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 115)

[CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg², Aib^4>28, Cpa⁶, Abu¹⁵, A6c²³, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 116)

[CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Abu¹⁵, A6c²³, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 117) [CH₃-(CH₂)_S-C(O)-TyT¹, D-VaI², Aib⁴'²⁸, Cpa⁶, Abu¹⁵, A6c²³, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 118)

[CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Abu¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 119)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Cpa⁶, Abu¹⁵, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 120) [CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg²'²⁸, Aib⁴, Cpa⁶, Abu¹⁵, NIe²⁷, hArg²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 121)

[D-Arg², Aib⁴'²⁸, des-Phe⁶, Abu¹⁵, A6c²³, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 122) [4-biphenylcarboxyl-Tyr¹, Ape², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; or (SEQ ID NO: 123)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Cpa⁶, His¹¹'²⁰, Abu¹⁵, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 125) or a pharmaceutically acceptable salt thereof.

4. A compound of claim 2, wherein A² is an achiral amino acid, or a pharmaceutically acceptable salt thereof.

5. A compound of claim 4, wherein A² is Ape, Act, Ace, or Aib; or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 5, wherein said compound is: [Ph-CH₂-C(O)-TyT¹, Ape², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 54) [Ac-Tyr¹, Ape², Aib⁴"²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 55) [Ph-CH₂-C(O)-TyT¹, Ape², Aib²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 56) [Ac-Tyr¹, Ape², Aib²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 57)

[Ph-CH₂-C(O)-TyT¹, Aib², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 69) [CH₃-(CH₂)_I2-C(O)-TyT¹, Aib²'⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 92) [CH₃-(CH₂),o-C(0)-Tyr¹, Aib²'⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 94) [4-biphenylcarboxyl-Tyr¹, Aib²'⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 107) [CH₃-(CH₂)_S-C(O)-TyT¹ , Aib²'⁴'²⁸, Cpa⁶, Abu¹⁵, A6c²³, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 114)

[CH₃-(CH₂)_S-C(O)-TyT¹, Aib²'⁴'²⁸, Abu¹⁵, A6c²³, NIe²⁷JhGHRH(I -29)NH₂; or (SEQ ID NO: 115)

[4-biphenylcarboxyl-Tyr¹, Ape², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 123) or a pharmaceutically acceptable salt thereof.

7. A compound of claim 2, wherein A² is a D-amino acid, or a pharmaceutically acceptable salt thereof.

8. A compound of claim 7, wherein A² is D-Arg, D-Orn, D-Dab, D-Dap, D-VaI, D-Leu, D-Phe, D-Trp, D-Tyr, D-Ser, D-Thr, D-GIu, D- Asp, or D-AIa; or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 8, wherein said compound is: [Ac-Tyr¹, D-Arg², NIe²⁷, Aib²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 2)

[Ph-CH₂-C(O)-TyT¹, D-Arg², A6c²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 3) [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c²⁶, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 4) [Ac-Tyr¹, D-Arg², A6c²⁶, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 5) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib²⁵, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 6) [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c²³, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 7) [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c²², NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 8) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib¹⁹, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 9) [Ph-CH₂-C(O)-TyT¹, D-Arg², NIe²⁷, Aib²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 10) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib¹⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 11) [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c¹⁷, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 12) [Ph-CH₂-C(O)-TyT¹, D-Arg², A5c¹³, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 13) [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 14) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 15) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib³, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 16) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 17) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁹, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 18) [Ph-CH₂-C(O)-TyT¹, D-Arg², A6c¹⁴, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 19) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 20) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁷, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 21)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Cpa⁶, Amp⁹, Mop¹⁰, Abu¹⁵, A6c²³, NIe²⁷, D-Arg²⁸, hArg²⁹] hGHRH(l-29)NH₂; (SEQ ID NO: 22)

[Ph-CH₂-C(O)-TyT¹, D-Arg²'²⁸, Cpal⁶, hArg⁹'²⁹, Amp¹⁰, Abu¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 23)

[D-Arg²'²⁸, Cpal⁶, hArg⁹'²⁹, Amp¹⁰, Abu¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 24) [Ac-Tyr¹, D-Arg², Aib⁴'²⁵'²⁸, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 25) [Ac-Tyr¹, D-Arg², Aib³'²⁸, Brp⁶, Abu¹⁵, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 26) [Ac-Tyr¹, D-Arg², Aib⁴'²⁸, Brp⁶, Abu¹⁵, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 27)

[Ac-Tyr¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 29) [Ac-Tyr¹, D-Arg², Aib⁴, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 30)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Cpa⁶, Abu¹⁵, A6c²³, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 31)

[Ac-Tyr¹, D-Arg², Aib⁴'²⁸, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 32) [D-Arg², Aib⁴'²⁸, Cpa⁶, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 33) [Ac-Tyr¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 34)

[Ac-Tyr¹, D-Arg², β-Ala¹⁵, Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 35) [Ac-Tyr¹, D-Arg², Aib⁴'²⁸, Cpa⁶, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 36)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, Cpa⁶, Abu¹⁵, NIe²⁷, D-Arg²⁸, hArg²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 37) [Ph-CH₂-C(O)-TyT¹, D-Arg², Cpa⁶, hArg⁹, Mop¹⁰, Abu¹⁵, NIe²⁷, D-Arg²⁸, hArg²⁹]hGHRH(l- 29)NH₂; (SEQ ID NO: 38)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 39) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷, Act²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 40) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷, A5c²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 41) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Amp¹⁰, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 42) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Cpal⁶, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 43) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, β-Ala¹⁵, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 44) [Ph-CH₂-C(O)-TyT¹, D-Lys², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 45) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Ape¹¹, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 46) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Ape¹², Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 47) [CH₃-(CH₂)_I2-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 48) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷, Lys(N^ε-tetradecanoyl)²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 49)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Lys(N^ε-tetradecanoyl)¹², Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 51)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Lys^-tetradecanoyl)¹¹, Arg¹²'²¹, NIe²⁷JhGHRH(I- 29)NH₂; (SEQ ID NO: 52)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Apn¹⁵, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 53) [(CH₃)₂CH-C(O)-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷J hGHRH(l-29)NH₂; (SEQ ID NO: 58) [CH₃-(CH₂)₂-C(O)-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 59) [4-chlorocinnamoyl-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 60) [trans-cinnamoyl-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 61) [p-tolylacetyl-Tyr¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 62) [2-indolecarboxyl-Tyr¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 63) [2-naphthoyl-Tyr¹, D-Arg², Aib⁴'²⁸, Nle²⁷JhGHRH(l-29)NH₂; (SEQ ID NO: 64) [1-naphthoyl-Tyr¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 65) [4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 66) ^-(p-toly^-propionyl-Tyr¹, D-Arg², Aib⁴'²⁸, Nle²⁷JhGHRH(l-29)NH₂; (SEQ ID NO: 67) [trimethylacetyl-Tyr¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 68) [Ph-CH₂-C(O)-TyT¹, D-Orn², Aib^4>28, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 70) [Ph-CH₂-C(O)-TyT¹, D-Dab², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 71) [Ph-CH₂-C(O)-TyT¹, D-Dap², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 72) [Ph-CH₂-C(O)-TyT¹, D-VaI², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 73) [Ph-CH₂-C(O)-TyT¹, D-Leu², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 74) [Ph-CH₂-C(O)-TyT¹, D-Phe², Aib⁴"²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 75) [Ph-CH₂-C(O)-TyT¹, D-Trp², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 76) [Ph-CH₂-C(O)-TyT¹, D-Tyr², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 77) [Ph-CH₂-C(O)-TyT¹, D-Ser², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 78) [Ph-CH₂-C(O)-TyT¹, D-Thr², Aib⁴"²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 79) [Ph-CH₂-C(O)-TyT¹, D-GIu², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 80) [Ph-CH₂-C(O)-TyT¹, D-Asp², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 81) [Ph-CH₂-C(O)-TyT¹, D-AIa², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 82) [CH₃-(CH₂)_I0-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 83) [CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg², Aib^4>28,Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 84) [CH₃-(CH₂)_O-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 85) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 86) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Leu²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 87) [CH₃-(CHz)₁₂-C(O)-TyT¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 88) [Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 89) [CH₃-(CH₂)I₂-C(O)-TyT¹, D-Arg², Aib⁴, NIe²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 90) [CH₃-(CH₂)₄-C(O)-Tyr¹, D-Arg², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 91) [CH₃-(CH₂)_J2-C(O)-TyT¹, D-VaI², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 93) [CH₃-(CH₂VC(O)-TyT¹, D-VaI², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 95) [CH₃-(CH₂)_K)-C(O)-TyT¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 96)

[CH₃-(CH₂)₆-C(O)-Tyr¹, D-Arg², β-Ala¹⁵, Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 97)

[CH₃-(CH₂)_K)-C(O)-TyT¹, D-VaI², Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 98) [CH₃-(CH₂)₁₂-C(O)-Tyr¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 99) [CH₃-(CH₂VC(O)-TyT¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 100) [CH₃-(CH₂VC(O)-TyT¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 101) [CH₃-(CH₂)₁₂-C(O)-Tyr¹, D-Arg², β-Ala¹⁵, Aib⁴'²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 102)

[Ph-CH₂-C(O)-HiS¹, D-Arg²'²⁸, Cpa⁶, Arg⁹, Abu¹⁵, NIe²⁷, hArg²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 103)

[4-biphenylcarboxyl-Tyr¹, D-VaI², Aib⁴-²⁸, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 104) [4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴, NIe²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 105)

[4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴'²⁸, β-Ala¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 106)

[4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁸]hGHRH(l-29)NH₂; (SEQ ID NO: 108) [4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴, Leu²⁷, Apc²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 109)

[4-biphenylcarboxyl-Tyr¹, D-Arg², Aib⁴, NIe²⁷, Apc²⁹]hGHRH(l-29)NH₂; (SEQ ID NO: 110) [H-Tyr¹, D-Arg², A6c²⁶, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 111) [H-Tyr¹ _rD-Arg^?, Aib²⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 112) [H-Tyr¹, D-Arg², A6c²³, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 113)

[CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Cpa⁶, Abu¹⁵, A6c²³, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 116) [CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Abu¹⁵, A6c²³, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 117)

[CH₃-(CH₂)_S-C(O)-TyT¹, D-VaI², Aib⁴'²⁸, Cpa⁶, Abu¹⁵, A6c²³, NIe²⁷JhGHRH(I -29)NH₂; (SEQ ID NO: 118) [CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Abu¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ED NO: 119)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Cpa⁶, Abu¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ID NO: 120)

[CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg²'²⁸, Aib⁴, Cpa⁶, Abu¹⁵, NIe²⁷, hArg²⁹]hGHRH(l-29)NH₂; (SEQ ED NO: 121) [D-Arg², Aib⁴'²⁸, des-Phe⁶, Abu¹⁵, A6c²³, Nle²⁷]hGHRH(l-29)NH₂; or (SEQ ED NO: 122)

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Cpa⁶, His¹¹'²⁰, Abu¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ED NO: 125) or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 9, wherein said compound is:

[Ph-CH₂-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Cpa⁶, Abu¹⁵, A6c²³, NIe²⁷JhGHRH(I -29)NH₂; or (SEQ ED NO: 31)

[CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Abu¹⁵, NIe²⁷J hGHRH(l-29)NH₂; (SEQ ED NO: 119) or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 10, wherein said compound is:

[CH₃-(CH₂)_S-C(O)-TyT¹, D-Arg², Aib⁴'²⁸, Abu¹⁵, Nle²⁷]hGHRH(l-29)NH₂; (SEQ ED NO: 119) or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of any of claims 1 to 11.

13. The composition of claim 12, further comprising a pharmaceutically acceptable carrier.

14. A method of determining a compound's ability to bind to a GHRH receptor, said method comprising the step of measuring the ability of a compound to effect binding of a compound of any of claims 1 to 11 to said receptor, to a fragment of said receptor, to a polypeptide comprising said fragment of said receptor, to a splice variant of said receptor, or to a derivative of said polypeptide.

15. A method of screening for a GHRH antagonist, said method comprising the step of using a compound of any of claims 1 to 11, or a pharmaceutically acceptable salt thereof, to produce GHRH receptor activity and then measuring the ability of a test compound to alter GHRH receptor activity.

16. A method for achieving a beneficial effect in a subject, said method comprising the step of administering to said subject an effective amount of a compound of any of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, wherein said effective amount is effective for producing a beneficial effect in helping to treat or helping to prevent a disease or disorder.

17. The method of claim 16, wherein said disease or disorder is selected from the group consisting of diabetic retinopathy, diabetic nephropathy, and acromegaly.

18. Use of a compound of any of claims 1 to 11 , for the preparation of a pharmaceutical composition for suppressing growth hormone levels in a patient in need thereof.

19. Use of a compound of any of claims 1 to 11, for the preparation of a pharmaceutical composition for suppressing levels of IGF-I or IGF-II in the tumor tissue of a patient having a cancer carrying receptors for IGF-I.

20. Use of a compound of any of claims 1 to 11 , for the preparation of a pharmaceutical composition for suppressing VEGF levels in the tumor tissue of a patient having a cancer.

21. Use of a compound of any of claims 1 to 11 , for the preparation of a pharmaceutical composition for suppressing serum levels of IGF-I in a patient having a cancer carrying receptors for IGF-I.

22. Use of a compound of any of claims 1 to 11 , for the preparation of a pharmaceutical composition for suppressing growth hormone levels in a patient having a cancer carrying receptors for IGF-I or growth hormone.

23. Use of a compound of any of claims 1 to 11, for the preparation of a pharmaceutical composition for blocking GHRH receptors in a patient having a cancer carrying receptors for

GHRH.

24. A method of suppressing growth hormone levels in a patient in need thereof, said method comprising the step of administering to said patient an effective amount of a compound of any of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

25. A method of suppressing levels of IGF-I or IGF-II in the tumor tissue of a patient having a cancer carrying receptors for IGF-I, said method comprising the step of administering to said patient an effective amount of a compound of any of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

26. A method of suppressing VEGF levels in the tumor tissue of a patient having a cancer, said method comprising the step of administering to said patient an effective amount of a compound of any of claims 1 to 11 , or a pharmaceutically acceptable salt thereof.

27. A method of suppressing serum IGF-I levels in a patient having a cancer carrying receptors for IGF-I, said method comprising the step of administering to said patient an effective amount of a compound of any of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

28. A method of suppressing growth hormone levels in a patient having a cancer carrying receptors for IGF-I or growth hormone, said method comprising administering to said patient an effective amount of a compound of any of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

29. A method of treating a patient having a cancer carrying receptors for GHRH, said method comprising the step of administering to said patient an amount of a compound of any of claims 1 to 11, or a pharmaceutically acceptable salt thereof, effective to block said GHRH receptors.

30. A method according to claim 29, wherein said cancer is selected from the group consisting of breast cancer, small cell lung cancer, and prostate cancer.