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. Although it has been demonstrated that the receptors which mediate this action are located in the periphery and are of the CCK-A subtype, their anatomical location has not been firmly established. A dense population 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 of 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 compounds to inhibit the actions of CCK-8 to produce satiety in the rat; this comparison supports the contention that CCK receptors of the rat pyloric sphincter could in part mediate the satiety effect produced by exogenous CCK-8.
Murphy
R B
RB
Department of Psychiatry, Cornell University Medical College, New York Hospital-Cornell Medical Center, White Plains 10605.
Smith
G P
GP
Schneider
L H
LH
Gibbs
J
J
D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002766:Cholecystokinin / Q000031:analogs & derivatives*; D020109:Devazepide; D004305:Dose-Response Relationship, Drug; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011377:Proglumide / Q000031:analogs & derivatives / Q000494:pharmacology; D011708:Pylorus / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012527:Satiation / Q000187:drug effects / Q000502:physiology*; D012844:Sincalide / Q000494:pharmacology
D001570:Benzodiazepinones; D002766:Cholecystokinin; C075387:phenoxyacetylproglumide; D011377:Proglumide; D020109:Devazepide; C048181:lorglumide; D012844:Sincalide