Structure-activity studies of reduced-size gonadotropin-releasing hormone agonists derived from the sequence of an endothelin antagonist.
We have previously determined that Ac-D-Trp-Leu-Asp-Ile-Ile-Trp (peptide I), an endothelin antagonist, binds specifically (Ki = 1.9 microM) to the rat pituitary gonadotropin-releasing hormone (GnRH) receptor. Moreover, peptide I exhibits a GnRH agonistic activity, mediated directly by the GnRH receptor. We now report structure-activity studies of peptide I in respect to its interactions with the GnRH receptor. Our studies suggest that the bioactive conformation of peptide I, recognized by the GnRH receptor, is of a cyclic nature. Thus cyclic analogues of peptide I exhibit higher affinity to the GnRH receptor and increased agonistic potencies as compared to peptide I itself. A linear peptide, Ile-Ile-Trp-D-Trp-Leu-Asp, which presumably forms a similar cyclic conformation, was also shown to be a GnRH agonist. Intraperitoneal administration of Ac-Ile-Ile-Trp-D-Trp-Leu-Cys-OH (Ki = 0.32 microM), one of the cyclic hexapeptides that we have synthesized, to rats induces secretion of luteinizing hormone (LH) with a potency which is only 1 order of magnitude less than that of GnRH itself. Moreover, plasma levels of LH remained elevated for a longer period of time following the administration of the cyclic hexapeptide. This novel class of GnRH agonists may prove useful in the development of new therapeutics.
Yahalom
D
D
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel.
Rahimipour
S
S
Koch
Y
Y
Ben-Aroya
N
N
Fridkin
M
M
D000818:Animals; D001921:Brain / Q000378:metabolism; D016232:Endothelins / Q000037:antagonists & inhibitors*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists*; D066298:In Vitro Techniques; D007986:Luteinizing Hormone / Q000378:metabolism; D013058:Mass Spectrometry; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000378:metabolism; D011966:Receptors, LHRH / Q000378:metabolism; D013329:Structure-Activity Relationship
D016232:Endothelins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D011966:Receptors, LHRH; C412729:acetyl-tryptophyl-leucyl-aspartyl-isoleucyl-isoleucyl-tryptophan; C412728:cyclo(acetyl-isoleucyl-isoleucyl-tryptophyl-tryptophyl-leucyl-cysteinyl); D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone