CR-2945 - A NOVEL CCKB RECEPTOR ANTAGONIST WITH ANXIOLYTIC-LIKE ACTIVITY

The effects of CR 2945, an antranilic acid derivative member of a nove l 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 t he CCKB over the CCKA receptor. In ex-vivo binding studies, CR 2945, a fter i.v. and s.c. administration, inhibited the binding of [I-125] (B H). CCK8 in rat cortex homogenate with ID(50)s Of 10.9 mg/kg and 13.5 mg/kg, respectively. In four rodent tests of anxiety (mouse black/whit e box, rat elevated plus-maze, rat elevated zero-maze and punished lic king test in the rat) CR 2945 (0.1-10 mg/kg s.c. or orally) showed sig nificant dose-dependent anxiolytic-like effects. The reference CCKB an tagonist compounds CAM-1028 and L-365,260 showed an anxiolytic-like ac tivity less robust than that of CR 2945 in the elevated zero-maze afte r s.c. administration, and these compounds were inactive in the elevat ed plus-maze after oral administration. The magnitude of the activity of CR 2945 was comparable to that of diazepam, but without signs of se dation and ataxia. Furthermore, a 7-day repeated treatment with CR 294 5 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 do se-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 su ggest that CR 2945 might be a promising alternative to the existing th erapy of anxiety-related disorders. Behav Pharmacol 1998; 9:183-194 (C ) 1998 Lippincott-Raven Publishers.