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 (K-i = 1.9 mu M) to the rat pituitary gonadotropin-releasing hormone (GnRH) receptor. Moreover, peptide I exhibits a GnRH agonistic activity, mediated directly by the GnRH recept or. We now report structure-activity studies of peptide I in respect to its interactions with the GnRH receptor. Our studies suggest that the bioactiv e conformation of peptide I, recognized by the GnRH receptor, is of a cycli c nature. Thus cyclic analogues of peptide I exhibit higher affinity to the GnRH receptor and increased agonistic potencies as compared to peptide I i tself. A linear peptide, ne-Ile-Trp-D-Trp-Leu-Asp, which presumably forms a similar cyclic conformation, was also shown to be a GnRH agonist. Intraper itoneal administration of Ac-Ile-Ile-Trp-D-Trp-Leu-Cys-OH (K-i = 0.32 mu M) , 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 r emained elevated for a longer period of time following the administration o f the cyclic hexapeptide. This novel class of GnRH agonists may prove usefu l in the development of new therapeutics.