SR146131: A New Potent, Orally Active, and Selective Nonpeptide Cholecystokinin Subtype 1 Receptor Agonist. II: In Vivo Pharmacological Characterization

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 289; no. 2; p. 752
• Main Authors: Bignon, E, Alonso, R, Arnone, M, Boigegrain, R, Brodin, R, Gueudet, C, Héaulme, M, Keane, P, Landi, M, Molimard, J C, Olliero, D, Poncelet, M, Seban, E, Simiand, J, Soubrié, P, Pascal, M, Maffrand, J P, Le Fur, G
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.05.1999
• Subjects: Animals; Appetite Stimulants - pharmacology; Callithrix; Cerebellum - drug effects; Cerebellum - metabolism; Cyclic GMP - metabolism; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced - drug therapy; Eating - drug effects; Female; Gallbladder Emptying - drug effects; Gastric Acid - secretion; Gastric Emptying - drug effects; Gerbillinae; Indoles - antagonists & inhibitors; Indoles - pharmacology; Male; Mice; Motor Activity - drug effects; Neuropeptide Y - pharmacology; Paraventricular Hypothalamic Nucleus - cytology; Paraventricular Hypothalamic Nucleus - drug effects; Paraventricular Hypothalamic Nucleus - metabolism; Proto-Oncogene Proteins c-fos - biosynthesis; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Receptors, Cholecystokinin - agonists; Species Specificity; Stereotyped Behavior - drug effects; Thiazoles - antagonists & inhibitors; Thiazoles - pharmacology
• ISSN: 0022-3565; 1521-0103

SR146131 is a potent and selective agonist at cholecystokinin subtype 1 (CCK 1 ) receptors in vitro. The present study evaluates the activity of the compound in vivo. SR146131 completely inhibited gastric and gallbladder emptying in mice (ED 50 of 66 and 2.7 μg/kg p.o., respectively). SR146131 dose dependently reduced food intake in fasted rats (from 0.1 mg/kg p.o.), in nonfasted rats in which food intake had been highly stimulated by the administration of neuropeptide Y (1–36) (from 0.3 mg/kg p.o.), in fasted gerbils (from 0.1 mg/kg p.o.), and in marmosets maintained on a restricted diet (from 3 mg/kg p.o.). SR146131 (10 mg/kg p.o.) also increased the number of Fos-positive cells in the hypothalamic paraventricular nucleus of rats. Locomotor activity of mice was reduced by orally administered SR146131 (from 0.3 mg/kg p.o.). When administered intrastriatally, SR146131 elicited contralateral turning behavior in mice. Furthermore, orally administered SR146131 (0.3–10 mg/kg), also reduced the levels of cerebellar cyclic GMP. Finally, SR146131 (0.1 μg/kg to 1 mg/kg, p.o.) significantly and dose dependently antagonized fluphenazine-induced mouth movements in rats. The CCK 1 antagonist SR27897B prevented all the effects of SR146131. Conversely, SR146131 was unable to elicit any agonist or antagonist effects in a model of CCK 2 receptor stimulation in vivo. SR146131 is a very potent and selective nonpeptide CCK 1 agonist in vivo. SR146131 is more potent than any other CCK 1 agonists reported to date. Because pharmacodynamic studies suggest that SR146131 should have a high absolute bioavailability, it may be a promising drug for the treatment of eating and motor disorders in humans.