Small synthetic ligands of the cholecystokinin-B/gastrin receptor can mimic the function of endogenous peptide hormones

The gastric cholecystokinin-B/gastrin receptor (CCK-BR) is a key regulator of enterochromaffin-like cell function and proliferation. Over the last dec ade, a number of small non-peptide CCK-BR "antagonists" have been discovere d. Here, we demonstrate that some of these non-peptide ligands in fact poss ess significant ability to activate the human CCK-BR, and are, therefore, m ore properly categorized as partial agonists. When tested in COS-7 cells tr ansiently expressing the recombinant human CCK-BR, saturating concentration s of the small "peptoid" ligands PD 135,158 and PD 136,450 stimulated inosi tol phosphate formation to 23 and 43 percent, respectively, of the maximum response induced by a considerably larger endogenous peptide agonist, chole cystokinin octapeptide. In contrast, the benzodiazepine-derived CCK-BR liga nd, YM022, acted as a "true" high-affinity antagonist of cholecystokinin-in duced inositol phosphate formation (pA(2) = 9.69). Consistent with recent f indings in animal experiments, our data reveal that small synthetic ligands have the potential to function as either CCK-BR agonists or antagonists. T hese dual properties of synthetic molecules must be considered when evaluat ing candidate drugs for human disease.