Vol. 289, Issue 2, 752-761, May 1999

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

Eric Bignon, Richard Alonso¹, Michèle Arnone, Robert Boigegrain¹, Roger Brodin¹, Christiane Gueudet¹, Michel Héaulme¹, Peter Keane, Marco Landi², Jean-Charles Molimard¹, Dominique Olliero¹, Martine Poncelet¹, Eric Seban, Jacques Simiand, Philippe Soubrié¹, Marc Pascal, Jean-Pierre Maffrand and Gérard Le Fur¹

Sanofi Recherche, 195 Toulouse Cedex, France

SR146131 is a potent and selective agonist at cholecystokinin subtype 1 (CCK₁) receptors in vitro. The present study evaluates the activity of the compound in vivo. SR146131 completely inhibited gastric and gallbladder emptying in mice (ED₅₀ 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 CCK₁ antagonist SR27897B prevented all the effects of SR146131. Conversely, SR146131 was unable to elicit any agonist or antagonist effects in a model of CCK₂ receptor stimulation in vivo. SR146131 is a very potent and selective nonpeptide CCK₁ agonist in vivo. SR146131 is more potent than any other CCK₁ 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.