PERIPHERAL FACTORS IN THE MEDIATION OF CHOLECYSTOKININ-INDUCED SATIETY AS ASSESSED BY COMPARATIVE POTENCIES OF CHOLECYSTOKININ ANTAGONISTS

Cholecystokinin COOH-terminal octapeptide (CCK-8) produces a satiating effect in the rat and other animals upon peripheral administration. A lthough it has been demonstrated that the receptors which mediate this action are located in the periphery and are of the CCK-A subtype, the ir anatomical location has not been firmly established. A dense popula tion of CCK receptors in the pyloric sphincter has been suggested as a candidate. We here quantify the potency of several CCK antagonists to inhibit the contractile effect of CCK-8 on the rat pyloric sphincter in vitro. The potent and selective antagonist MK-329 has a Schild pK o f 8.85; the less potent but selective antagonist lorglumide (CR-1409) a pK of 6.37; the related antagonist phenoxyacetylproglumide (phi-oAc proglumide) a pK of 5.1; and the weak parent compound proglumide a pK of about 3.3. These data can be compared with the potencies of these c ompounds to inhibit the actions of CCK-8 to produce satiety in the rat ; this comparison supports the contention that CCK receptors of the ra t pyloric sphincter could in part mediate the satiety effect produced by exogenous CCK-8.