title: A71378: a CCK agonist with high potency and selectivity for CCK-A receptors.
abstract: Receptors for the brain and gut peptide cholecystokinin (CCK) have been classified into two classes, CCK-A and CCK-B. To date, peptide analogues with selectivity for the CCK-B receptors have been identified, and selective antagonists for CCK-A and CCK-B receptors have been reported as well; until now, there have been no reports of highly selective CCK-A agonists. Herein we describe the properties of A71378 [desamino-Try(SO3H)-Nle-Gly-Trp-Nle-(N-methyl)Asp-Phe-NH2], a highly selective CCK-A receptor ligand. Characterization of A71378 was carried out in the guinea pig pancreas, cortex, gastric gland, and ileum, as well as in NCI-H345 cells. The IC50 values of A71378 for the pancreatic CCK-A, cortical CCK-B, and gastrin receptor were 0.4 nM, 300 nM, and 1,200 nM, respectively. A71378 proved to be a potent agonist in eliciting pancreatic amylase secretion (EC50 = 0.16 nM) and ileal muscle contraction (EC50 = 3.7 nM). In contrast, A71378 was relatively weak (EC50 = 600 nM) in mobilizing intracellular calcium from NCI-H345 cells, which express CCK-B/gastrin receptors. The high potency and selectivity of A71378 for the CCK-A over CCK-B and gastrin receptors is unprecedented among CCK peptides. Studies on CCK-7 analogues indicate that N-methylation of the Asp residue is responsible for the observed selectivity for CCK-A receptors. This discovery of a selective CCK-A agonist should prove valuable for studies aimed at understanding the physiological roles of CCK-A receptors in the brain and periphery.
authors.affiliation: Neuroscience Research Division, Abbott Laboratories, Abbott Park, Illinois 60064.
authors.forename: C W
authors.initials: CW
authors.lastname: Lin
authors.forename: M W
authors.initials: MW
authors.lastname: Holladay
authors.forename: D G
authors.initials: DG
authors.lastname: Witte
authors.forename: T R
authors.initials: TR
authors.lastname: Miller
authors.forename: C A
authors.initials: CA
authors.lastname: Wolfram
authors.forename: B R
authors.initials: BR
authors.lastname: Bianchi
authors.forename: M J
authors.initials: MJ
authors.lastname: Bennett
authors.forename: A M
authors.initials: AM
authors.lastname: Nadzan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism*; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism*; D007700:Kinetics; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D009928:Organ Specificity; D010179:Pancreas / Q000378:metabolism; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000378:metabolism*; D012844:Sincalide / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
chemical_list: D009842:Oligopeptides; D011949:Receptors, Cholecystokinin; C063897:A 71378; D012844:Sincalide; D002118:Calcium