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 (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 micrograms/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 microgram/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.
Bignon
E
E
Sanofi Recherche, 195 Toulouse Cedex, France. eric.bignon@sanofi.com
Alonso
R
R
Arnone
M
M
Boigegrain
R
R
Brodin
R
R
Gueudet
C
C
Héaulme
M
M
Keane
P
P
Landi
M
M
Molimard
J C
JC
Olliero
D
D
Poncelet
M
M
Seban
E
E
Simiand
J
J
Soubrié
P
P
Pascal
M
M
Maffrand
J P
JP
Le Fur
G
G
D000818:Animals; D019167:Appetite Stimulants / Q000494:pharmacology; D002144:Callithrix; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy; D004435:Eating / Q000187:drug effects; D005260:Female; D016473:Gallbladder Emptying / Q000187:drug effects; D005744:Gastric Acid / Q000378:metabolism; D005746:Gastric Emptying / Q000187:drug effects; D005849:Gerbillinae; D007211:Indoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009478:Neuropeptide Y / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000819:agonists*; D013045:Species Specificity; D013239:Stereotyped Behavior / Q000187:drug effects; D013844:Thiazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D019167:Appetite Stimulants; D007211:Indoles; D009478:Neuropeptide Y; D016760:Proto-Oncogene Proteins c-fos; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; C118846:SR 146131; D013844:Thiazoles; D006152:Cyclic GMP