Peptides, Vol. 9, Suppl. 1, pp. 207-214.© Pergamon Journals Ltd., 1988.Printedin the U.S.A. 0196-9781/88$3.00 + .00 Two Proglumide Analogues are Equipotent Antagonists of the Inhibition of Food Intake by CCK-8 LINDA H. SCHNEIDER, 1 RANDALL B. MURPHY AND GERARD P. SMITH Department of Psychiatry, Cornell University Medical College and the Edward W. Bourne Behavioral Research Laboratory, The Eating Disorders Institute The New York Hospital-Cornell Medical Center, Westchester Division, White Plains, NY 10605 and Department of Chemistry, New York University, New York, NY 10003 SCHNEIDER, L. H., R. B. MURPHY AND G. P. SMITH. Twoproglumide analogues are equipotent antagonists of the inhibition of food intake by CCK-8. PEPTIDES 9: Suppl. 1, 207-214, 1988.--The reduction in food intake produced by exogenous CCK-8 (8 /zg.kg 2, IP) in 18 hr food-deprived rats was significantly reversed by either of two proglumide analogues at doses of 0.44 and 4.4 p.M.kg -~. The two glutamic acid derivatives tested were CR-1409 [N-(3,4- dichlorobenzoyl)-L-glutamic acid-l-di-n-pentylamide], effective at doses of 0.2 and 2.0 mg-kg -~, IP, and PGDPA [N- (phenoxyacetyl)-L-glutamic acid-l-di-n-propylamide], effective at the equimolar doses of 0.16 and 1.6 mg.kg-t, IP, as well as at 16 mg.kg 1(44 #M.kg-~). By comparison, proglumide reversed the inhibition of food intake by CCK-8 at 160 mg-kg 1 (470/xM.kg ~), but not at 16 mg.kg-~ (47 txM.kg-J). At the 0.44 tzM.kg -~ 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-foldmore 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-foldmore potent than proglumide as an antagonist of the inhibitionof 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. CCK antagonist Proglumide Ingestion Satiety Food intake Peptide PERIPHERAL administration of the COOH-terminal oc- tapeptide of cholecystokinin (CCK-8), a major molecular form of the brain/gut peptide cholecystokinin (CCK), inhibits food intake and elicits the behavioral sequence that charac- terizes postprandial satiety [41]. The location of the popula- tion(s) of CCK receptors critical to the satiating effect of exogenous CCK-8 is unknown. Receptors for CCK are found in the pyloric sphincter [31, 37, 42], duodenum [32,37], ileum [34], antrum [1,37], lower esophageal sphincter [36], pancreatic acinar cell [16,18], gallbladder [4], vagus nerve [30,45] and within central pathways [2, 5, 9, 10, 17, 29, 43, 44]. To be considered a candidate receptor site for the media- tion of the satiating effect of CCK-8, the receptors must share two characteristics: (1) they must bind sulfated CCK-8 with much higher affinity than they bind desulfated CCK-8 (Type A receptors, [29]) because sulfated CCK-8 has a po- tent satiating effect, but desulfated CCK-8 does not [41]; and (2) the receptors must not be inside the blood-brain barrier, because peripherally administered CCK-8 does not cross the blood-brain barrier [8,35]. In the rat, CCK receptors with these characteristics are located on muscle cells in the pyloric sphincter [29,31] and antrum [1], on enteric neurons in the ileum [34], on pancreatic acinar cells [18], in cervical [45] and abdominal [30] vagal fibers, and on cells in the area postrema [29]. The lesion technique has been used to attempt to decide which of these five receptor sites is necessary for the satiat- ing effect of exogenous CCK-8. There is relevant data from lesions of all the sites except the pancreatic acinar cells and the intestinal neurons. The effect of removal of receptors in the pyloric sphincter appears to depend on the time of testing after surgical re- moval of the pylorus. Decreased satiating potency was ob- served when rats were tested 7-10 days after pylorectomy [28]; no change in satiating potency was observed when rats were tested 1-2 months after pylorectomy [13]. Lesions of the area postrema have been reported to de- 1Requests for reprints-should be addressed to Dr. Linda H. Schneider, Bourne Laboratory, NY Hospital-CorneU Medical Center, 21 Bloomingdale Road, White Plains, NY 10605. 207