title: Structure-activity relationship studies of gonadotropin-releasing hormone antagonists containing S-aryl/alkyl norcysteines and their oxidized derivatives.
abstract: A series of acyline analogues incorporating l- and d-isomers of S-arylated/alkylated norcysteines [Ncy(R), where R is 2-naphthyl, methyl, and isopropyl] at positions 1, 4, 7, and 10 were synthesized. Some of these analogues were mono- and dioxidized to sulfoxides and sulfones. All of the analogues of acyline were screened for the antagonism of the GnRH-induced response in a reporter gene assay in HEK-293 cells expressing the human GnRH receptor. Nine of the analogues (9, 11, 15, 16, 17, 19, 20, 21, and 22) had antagonistic potency (IC50 < 2 nM) similar to that of acyline (IC50 = 0.52 nM) in this assay. Selected analogues (9, 11, 15, 16, 19, and 21) were tested in vitro for their antagonism at the rat GnRH-R in a reporter gene assay as well as in an in vivo intact male rat assay. Analogues 9 and 15 were the most potent in suppressing testosterone levels.
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037, USA.
authors.forename: Manoj P
authors.initials: MP
authors.lastname: Samant
authors.forename: Richard
authors.initials: R
authors.lastname: White
authors.forename: Doley J
authors.initials: DJ
authors.lastname: Hong
authors.forename: Glenn
authors.initials: G
authors.lastname: Croston
authors.forename: P Michael
authors.initials: PM
authors.lastname: Conn
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Janovick
authors.forename: Jean
authors.initials: J
authors.lastname: Rivier
mesh_terms: D000818:Animals; D002087:Butyrates / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D017930:Genes, Reporter; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013237:Stereoisomerism; D013450:Sulfones / Q000138:chemical synthesis / Q000494:pharmacology; D013454:Sulfoxides / Q000138:chemical synthesis / Q000494:pharmacology; D013739:Testosterone / Q000037:antagonists & inhibitors / Q000097:blood
chemical_list: D002087:Butyrates; D009281:Naphthalenes; D009842:Oligopeptides; D013450:Sulfones; D013454:Sulfoxides; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007930:Leucine; D003545:Cysteine; C109238:acyline