title: Gastrin releasing peptide antagonists with improved potency and stability.
abstract: Gastrin releasing peptide (GRP) is a 27 amino acid peptide hormone which is homologous to the amphibian peptide bombesin. Two series of novel GRP antagonists were developed by C-terminal modification of N-acetyl-GRP-20-27 amide. Peptide derivatives within each series resist enzymatic degradation in serum and exhibit strong affinity for the GRP receptor. The first series of compounds replaces the Leu26-Met27 region of GRP with an alkyl ether N-acetyl-GRP-20-25-NH-[(S)-1-ethoxy-4-methyl-2-pentane], specifically blocked radiolabeled GRP binding with an IC50 of 6 nM. In the second series of antagonists the oxygen of the ether moiety is replaced with a methylene group, resulting in GRP antagonists which are equipotent to native GRP in receptor binding assays (IC50 = 2 nM) and are also resistant to proteolytic degradation in vitro. All of the C-terminally modified peptides tested blocked GRP-stimulated mitogenesis in Swiss 3T3 mouse fibroblasts. Representative compounds also blocked GRP-induced elevation of [Ca2+]i in human SCLC cells, and inhibited GRP-independent release of gastrin in vivo.
authors.affiliation: Department of Cancer Research, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: D C
authors.initials: DC
authors.lastname: Heimbrook
authors.forename: W S
authors.initials: WS
authors.lastname: Saari
authors.forename: N L
authors.initials: NL
authors.lastname: Balishin
authors.forename: T W
authors.initials: TW
authors.lastname: Fisher
authors.forename: A
authors.initials: A
authors.lastname: Friedman
authors.forename: D M
authors.initials: DM
authors.lastname: Kiefer
authors.forename: N S
authors.initials: NS
authors.lastname: Rotberg
authors.forename: J W
authors.initials: JW
authors.lastname: Wallen
authors.forename: A
authors.initials: A
authors.lastname: Oliff
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005260:Female; D019886:Gastrin-Releasing Peptide; D005755:Gastrins / Q000097:blood; D006801:Humans; D051379:Mice; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D005755:Gastrins; D010455:Peptides; D019886:Gastrin-Releasing Peptide