Two proglumide analogues are equipotent antagonists of the inhibition of food intake by CCK-8.

The reduction in food intake produced by exogenous CCK-8 (8 micrograms.kg-1, IP) in 18 hr food-deprived rats was significantly reversed by either of two proglumide analogues at doses of 0.44 and 4.4 microM.kg-1. The two glutamic acid derivatives tested were CR-1409 [N-(3,4-dichlorobenzoyl)-L-glutamic acid-1-di-n-pentylamide], effective at doses of 0.2 and 2.0 mg.kg-1, IP, and PGDPA [N-(phenoxyacetyl)-L-glutamic acid-1-di-n-propylamide], effective at the equimolar doses of 0.16 and 1.6 mg.kg-1, IP, as well as at 16 mg.kg-1 (44 microM.kg-1). By comparison, proglumide reversed the inhibition of food intake by CCK-8 at 160 mg.kg-1 (470 microM.kg-1), but not at 16 mg.kg-1 (47 microM.kg-1). At the 0.44 microM.kg-1 dose which antagonized CCK-8-induced satiety, neither PGDPA nor CR-1409 reduced the inhibition of food intake induced by bombesin, supporting the behavioral specificity of these CCK antagonists. Previous in vitro studies have shown that CR-1409 was approximately 4000-fold more potent than proglumide and PGDPA was 100-fold more potent than proglumide as antagonists of CCK-8-induced amylase secretion and binding in pancreatic acinar cells. Here, we found no potency difference between PGDPA and CR-1409; each was more than 1000-fold more potent than proglumide as an antagonist of the inhibition of food intake produced by CCK-8. This nonparallelism between the potencies of these antagonists at CCK receptors located upon pancreatic acinar cells and at CCK receptors involved in CCK-8-induced satiety suggests that the two receptor populations differ pharmacologically.