title: Small synthetic ligands of the cholecystokinin-B/gastrin receptor can mimic the function of endogenous peptide hormones.
abstract: The gastric cholecystokinin-B/gastrin receptor (CCK-BR) is a key regulator of enterochromaffin-like cell function and proliferation. Over the last decade, a number of small non-peptide CCK-BR "antagonists" have been discovered. Here, we demonstrate that some of these non-peptide ligands in fact possess significant ability to activate the human CCK-BR, and are, therefore, more properly categorized as partial agonists. When tested in COS-7 cells transiently expressing the recombinant human CCK-BR, saturating concentrations of the small "peptoid" ligands PD 135,158 and PD 136,450 stimulated inositol phosphate formation to 23 and 43 percent, respectively, of the maximum response induced by a considerably larger endogenous peptide agonist, cholecystokinin octapeptide. In contrast, the benzodiazepine-derived CCK-BR ligand, YM022, acted as a "true" high-affinity antagonist of cholecystokinin-induced inositol phosphate formation (pA2 = 9.69). Consistent with recent findings in animal experiments, our data reveal that small synthetic ligands have the potential to function as either CCK-BR agonists or antagonists. These dual properties of synthetic molecules must be considered when evaluating candidate drugs for human disease.
authors.affiliation: Division of Gastroenterology, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA. martin.beinborn@es.nemc.org
authors.forename: M
authors.initials: M
authors.lastname: Beinborn
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.forename: L
authors.initials: L
authors.lastname: DeMeo
authors.forename: E W
authors.initials: EW
authors.lastname: McBride
authors.forename: A S
authors.initials: AS
authors.lastname: Kopin
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology*; D019556:COS Cells / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020109:Devazepide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000378:metabolism*; D008024:Ligands; D008536:Meglumine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D018716:Molecular Mimicry; D034444:Peptoids; D010627:Phenethylamines / Q000378:metabolism / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001570:Benzodiazepinones; D006727:Hormone Antagonists; D007211:Indoles; D007295:Inositol Phosphates; D008024:Ligands; D034444:Peptoids; D010627:Phenethylamines; D010671:Phenylurea Compounds; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D011994:Recombinant Proteins; D001569:Benzodiazepines; C065600:PD 135158; C077645:PD 136450; C087260:YM 022; C058121:L 365260; D008536:Meglumine; D020109:Devazepide; D002118:Calcium