title: Design and synthesis of potent hexapeptide and heptapeptide gonadotropin-releasing hormone antagonists by truncation of a decapeptide analogue sequence.
abstract: A novel strategy for designing reduced-size analogues of the decapeptide gonadotropin-releasing hormone (GnRH) was developed. As opposed to previous attempts to delete residues from either of the peptide's termini, our approach is based upon the known importance of both C- and N-terminals of GnRH analogues for receptor recognition, whereas the central part of the molecule is replaced by a short spacer. The present truncation strategy was successful for generation of reduced-size hexapeptide and heptapeptide antagonists possessing potent antagonistic capacity. The same methodology was not suitable for the generation of reduced-size agonists, suggesting different conformational characteristics for GnRH agonists and antagonists. A heptapeptide antagonist designed by this method was shown to inhibit serum levels of luteinizing hormone in castrated rats in vivo. Structure-activity studies suggested that the structural preferences for GnRH receptor recognition are similar to those reported for decapeptide antagonists. Our studies resulted in a heptapeptide GnRH antagonist (Ac-D-Nal2-D-Cpa-D-Pal-Gly-Arg-Pro-D-Ala-NH2) with high receptor binding affinity (IC50 = 7 nM), as compared to that of GnRH itself (IC50 = 2 nM). The highest affinity of a hexapeptide antagonist that we have synthesized was somewhat lower (IC50 = 45 nM).
authors.affiliation: Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Yahalom
authors.forename: S
authors.initials: S
authors.lastname: Rahimipour
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: D000818:Animals; D015195:Drug Design; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007986:Luteinizing Hormone / Q000378:metabolism; D013058:Mass Spectrometry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D011966:Receptors, LHRH / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D011966:Receptors, LHRH; C412730:acetyl-2-naphthylalanyl-chlorophenylalanyl-1-oxohexadecyl-glycyl-arginyl-prolyl-alaninamide; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone