title: CR 2945: a novel CCKB receptor antagonist with anxiolytic-like activity.
abstract: The effects of CR 2945, an antranilic acid derivative member of a novel family of non-peptide CCKB receptor antagonists, have been compared with those of CAM-1028, an analogue of the CCKB receptor antagonist CI-988, L-365,260 a benzodiazepine derivative CCKB antagonist, CR 1795, an analogue of the CCKA receptor antagonist lorglumide and diazepam, a benzodiazepine receptor agonist, in several rodent screens sensitive to conventional anxiolytics. CR 2945 displayed nanomolar affinity for rat CCKB receptors and showed a selectivity ratio of about 9000 for the CCKB over the CCKA receptor. In ex-vivo binding studies, CR 2945, after i.v. and s.c. administration, inhibited the binding of [125I] (BH)-CCK8 in rat cortex homogenate with ID50s of 10.9 mg/kg and 13.5 mg/kg, respectively. In four rodent tests of anxiety (mouse black/white box, rat elevated plus-maze, rat elevated zero-maze and punished licking test in the rat) CR 2945 (0.1-10 mg/kg s.c. or orally) showed significant dose-dependent anxiolytic-like effects. The reference CCKB antagonist compounds CAM-1028 and L-365,260 showed an anxiolytic-like activity less robust than that of CR 2945 in the elevated zero-maze after s.c. administration, and these compounds were inactive in the elevated plus-maze after oral administration. The magnitude of the activity of CR 2945 was comparable to that of diazepam, but without signs of sedation and ataxia. Furthermore, a 7-day repeated treatment with CR 2945 at 10 mg/kg/day s.c. did not induce tolerance or withdrawal anxiety in rats. CR 1795 showed anxiolytic-like activity with a bell-shaped dose-response curve in the elevated zero-maze model in rats (0.1-10 mg/kg, orally and s.c.), whereas in the mouse black/white box test and in the rat elevated plus-maze test it was less effective. The results suggest that CR 2945 might be a promising alternative to the existing therapy of anxiety-related disorders.
authors.affiliation: Rotta Research Laboratorium SpA, Monza, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Revel
authors.forename: L
authors.initials: L
authors.lastname: Mennuni
authors.forename: P
authors.initials: P
authors.lastname: Garofalo
authors.forename: F
authors.initials: F
authors.lastname: Makovec
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology; D001569:Benzodiazepines / Q000134:cerebrospinal fluid / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010179:Pancreas / Q000378:metabolism; D004856:Postural Balance / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D011678:Punishment; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012890:Sleep / Q000187:drug effects
chemical_list: D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; C116183:CR 2945; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; D003975:Diazepam