SR146131: A new potent, orally active, and selective nonpeptide cholecystokinin subtype 1 receptor agonist. II: In vivo pharmacological characterization

SR146131 is a potent and selective agonist at cholecystokinin subtype 1 (CC K1) receptors in vitro. The present study evaluates the activity of the com pound in vivo. SR146131 completely inhibited gastric and gallbladder emptyi ng in mice (ED50 of 66 and 2.7 mu g/kg p.o., respectively). SR146131 dose d ependently reduced food intake in fasted rats (from 0.1 mg/kg p.o.), in non fasted rats in which food intake had been highly stimulated by the administ ration of neuropeptide Y (1-36) (from 0.3 mg/kg p.o.), in fasted gerbils (f rom 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-p ositive cells in the hypothalamic paraventricular nucleus of rats. Locomoto r activity of mice was reduced by orally administered SR146131 (from 0.3 mg /kg p.o.). When administered intrastriatally, SR146131 elicited contralater al turning behavior in mice. Furthermore, orally administered SR146131 (0.3 -10 mg/kg), also reduced the levels of cerebellar cyclic GMP. Finally, SR14 6131 (0.1 mu g/kg to 1 mg/kg, p.o.) significantly and dose dependently anta gonized fluphenazine-induced mouth movements in rats. The CCK, antagonist S R27897B prevented all the effects of SR146131. Conversely, SR146131 was una ble to elicit any agonist or antagonist effects in a model of CCK2 receptor stimulation in vivo. SR146131 is a very potent and selective nonpeptide CC K1 agonist in vivo. SR146131 is more potent than any other CCK1 agonists re ported to date, Because pharmacodynamic studies suggest that SR146131 shoul d have a high absolute bioavailability, it may be a promising drug for the treatment of eating and motor disorders in humans.