A71378: a CCK agonist with high potency and selectivity for CCK-A receptors

• Published in: The American journal of physiology Vol. 258; no. 4 Pt 1; pp. G648 - G651
• Main Authors: Lin, C W, Holladay, M W, Witte, D G, Miller, T R, Wolfram, C A, Bianchi, B R, Bennett, M J, Nadzan, A M
• Format: Journal Article
• Language: English
• Published: United States 01-04-1990
• Subjects: Amino Acid Sequence; Animals; Binding, Competitive; Calcium - metabolism; Gastric Mucosa - metabolism; Guinea Pigs; Ileum - metabolism; Kinetics; Molecular Sequence Data; Muscle, Smooth - metabolism; Oligopeptides - metabolism; Oligopeptides - pharmacology; Organ Specificity; Pancreas - metabolism; Receptors, Cholecystokinin - drug effects; Receptors, Cholecystokinin - metabolism; Sincalide - analogs & derivatives; Sincalide - metabolism; Sincalide - pharmacology
• ISSN: 0002-9513
• DOI: 10.1152/ajpgi.1990.258.4.g648

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.