title: Novel gonadotropin-releasing hormone antagonists with substitutions at position 5.
abstract: Gonadotropin-releasing hormone (GnRH) antagonists with high potency and improved duration of action are needed for potential clinical applications. We synthesized four new antagonists (2-5) of GnRH homologues to Azaline B (1), with a common core sequence of [Aph(X)5, D-Aph(Cbm)6]Azaline B. In these analogs, (X) contains hydrophobic aromatic moieties (like homoveratoyl in 2, homovanillyl in 3, 2,5-dimethoxyphenylacetyl in 4, and 3,5-dimethoxyphenylacetyl in 5) designed to improve the duration of action over that of Azaline B. These analogs were tested in vitro for their ability to antagonize the GnRH receptor and in vivo for duration of action in a castrated male rat assay. Analogs 2, 4, and 5 were potent in vitro, but were found to be short acting in vivo. However, analog 3 [Aph(Hvn)5,D-Aph(Cbm)6]Azaline B is a potent human GnRH receptor antagonist in vitro (IC50 1.47 nM) and exhibits a longer duration of action than azaline B.
authors.affiliation: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, CA 92037, USA.
authors.forename: Manoj P
authors.initials: MP
authors.lastname: Samant
authors.forename: Doley J
authors.initials: DJ
authors.lastname: Hong
authors.forename: Glenn
authors.initials: G
authors.lastname: Croston
authors.forename: Catherine
authors.initials: C
authors.lastname: Rivier
authors.forename: Jean
authors.initials: J
authors.lastname: Rivier
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D015394:Molecular Structure; D051381:Rats; D011966:Receptors, LHRH / Q000187:drug effects; D011994:Recombinant Proteins / Q000187:drug effects
chemical_list: D011966:Receptors, LHRH; D011994:Recombinant Proteins; C070464:azaline; D007987:Gonadotropin-Releasing Hormone