Structure-activity studies of reduced-size gonadotropin-releasing hormone agonists derived from the sequence of an endothelin antagonist

Dror Yahalom, Shai Rahimipour, Yitzhak Koch, Nurit Ben-Aroya, Mati Fridkin

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

We have previously determined that Ac-D-Trp-Leu-Asp-Ile-Ile-Trp (peptide I), an endothelin antagonist, binds specifically (K(i) = 1.9 μM) 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 (K(i) = 0.32 μM), 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.

Original languageEnglish
Pages (from-to)2824-2830
Number of pages7
JournalJournal of Medicinal Chemistry
Volume43
Issue number15
DOIs
StatePublished - 27 Jul 2000
Externally publishedYes

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