title: Are radioligand antagonist/agonist binding ratios in rat pancreas predictive of functional efficacy of cholecystokinin receptor agonists and antagonists?
abstract: Radioligand binding assays have been previously used to predict the relative efficacy of novel ligands. In the present study we have investigated whether for the cholecystokinin CCK-A receptors in the rat pancreas, the ratio of binding affinities for compounds for antagonist and agonist radioligands are predictive of functional activity. A number of classical cholecystokinin agonists, such as CCK-8S, caerulein, CCK-8DS, pentagastrin and CCK-4 had antagonist/agonist binding ratios of 4-fold or greater. All compounds behaved as full agonists in the stimulation of phosphatidylinositol (PI) turnover and increase in amylase secretion in rat pancreas. In contrast, compounds such as the benzodiazepine derivatives devazepide and L-365,260 had binding ratios of less than one and lacked agonist activity in either functional assay. Interestingly, the dipeptide derivative CI-988, which has been described as a selective CCK-B antagonist, was found to have an antagonist/agonist binding ratio of 1.5 for the CCK-A receptors in rat pancreas which was sufficiently high for this compound to behave as a full agonist in the amylase assay, although CI-988 did not exhibit agonist activity in the PI assay. These results suggest that the effective receptor reserve in the amylase assay is greater than that required to stimulate PI turnover, and that the selective peptoid CCK-B antagonist CI-988 has weak agonist activity at CCK-A receptors.
authors.affiliation: Merck, Sharp and Dohme Research Laboratories, Terlings Park, Harlow, UK.
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: K L
authors.initials: KL
authors.lastname: Chapman
authors.forename: A J
authors.initials: AJ
authors.lastname: Smith
authors.forename: I
authors.initials: I
authors.lastname: Bailey
authors.forename: S B
authors.initials: SB
authors.lastname: Freedman
mesh_terms: D000818:Animals; D001570:Benzodiazepinones / Q000378:metabolism; D020109:Devazepide; D006727:Hormone Antagonists / Q000378:metabolism; D007700:Kinetics; D008297:Male; D018697:Nootropic Agents / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism*; D034444:Peptoids; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D012844:Sincalide / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: C090019:8-sulfocholecystokinin octapeptide; D001570:Benzodiazepinones; D006727:Hormone Antagonists; D018697:Nootropic Agents; D034444:Peptoids; D010716:Phosphatidylinositols; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; D020109:Devazepide; D012844:Sincalide