CL 284,846, a novel sedative‐hypnotic: Evaluation of its metabolites for pharmacological activity in vitro and in vivo

Abstract

AbstractCL 284,846, N‐[3‐3‐cyanopyrazolo[1,5‐a]pyrimidin‐7‐yl(phenyl)]‐N‐ethylacetamide, is a novel non‐benzodiazepine sedative‐hypnotic with benzodiazepine‐like sedative effects, but with less apparent liability for accompanying undesired side effects. Three metabolites of the parent sedative‐hypnotic have been isolated and identified, a desethyl metabolite, CL 284,859, a desethyl‐5‐keto metabolite, CL 345,644, and a 5‐keto metabolite, CL 345,905. In experiments to determine the ability of these compounds to displace [3H]‐flunitrazepam from rat cortical benzodiazepine receptors, the IC50 values were 205 nM for CL 284,846 compared to 4.5 nM for diazepam as a positive control, and 11 μM for CL 284,859. The other two metabolite, CL 345,644 and CL 345,905, failed to displace [3H]‐flunitrazepam. In a second experiment designed to evaluate in vivo receptor‐mediated activity, CL 284,846 (3.0 mg/kg; 9.836 μmol/kg) was established as a discriminative stimulus (DS) in rats. While CL 284,846 (0.03ndash;3.0 mg/kg; 0.098–9.836 μmol/kg) showed a doserelated increase in drug‐appropriate responding and one dose of triazolam (0.3 mg/kg; 0.875 μmol/kg) substituted as a positive control, all three metabolites (3.0–100.0 mg/kg; 10.3–341.3 μmol/kg for CL 284,859; 6.0–201.2 μmol/kg for CL 345,644; 9.3–311.5 μmol/kg for CL 345,905) failed to substitute for the DS effects of CL 284,846. These results suggest that CL 284,859, CL 345,644, and CL 345,905, the metabolites of the sedative‐hypnotic CL 284,846, have no significant neuropharmacological effects at central benzodiazepine receptors and, thus, do not contribute to the activity of the parent compound. © 1994 Wiley‐Liss, Inc.