title: Hexapeptide and cyclic pentapeptide endothelin antagonists directly activate pituitary gonadotropin-releasing hormone receptors.
abstract: In the course of our studies toward the development of novel analogs of the decapeptide gonadotropin releasing hormone (GnRH), we have examined a hexapeptide that is an antagonist of endothelin (ET). It was found that this peptide, Ac-D-Trp-Leu-Asp-Ile-Ile-Trp (peptide 1), binds specifically to the pituitary GnRH receptor. Moreover, peptide 1 exhibits a GnRH agonistic activity (i.e., it induces luteinizing hormone release from rat pituitary). This activity is mediated directly by the GnRH receptor and is suppressed by a GnRH antagonist. Removal of the acetyl group of peptide 1 results in a hexapeptide (peptide 2) with binding properties similar to those of GnRH but with a diminished affinity toward the ET receptor. Several other ET antagonists were screened for a potential interaction with the GnRH receptor. Two of these, the hexapeptide PD145065 and the cyclic pentapeptide BQ-123, expressed GnRH agonistic activity at micromolar concentrations in vitro. BQ-123, previously approved for trials on humans as an ET antagonist, is demonstrated to act in vivo as a GnRH agonist, in a dose that was demonstrated previously as the minimal required dose for significant ET antagonism. The GnRH agonistic activity of ET antagonists may therefore result in interference with the physiological control of the reproductive system. Such effects may be most severe when ET antagonists are used chronically. Thus, the major practical message of this study is the need to circumvent the potential side effects of ET antagonist-based drugs.
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Yahalom
authors.forename: Y
authors.initials: Y
authors.lastname: Koch
authors.forename: N
authors.initials: N
authors.lastname: Ben-Aroya
authors.forename: M
authors.initials: M
authors.lastname: Fridkin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011966:Receptors, LHRH / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D016232:Endothelins; D009842:Oligopeptides; D010446:Peptide Fragments; D011966:Receptors, LHRH; C061533:endothelin (16-21)