Pharmacological and behavioral characterization of the novel CRF1 antagonist BMS-763534

Abstract BMS-763534 is a potent (CRF 1 IC 50  = 0.4 nM) and selective (>1000-fold selectivity vs. all other sites tested) CRF 1 receptor antagonist (pA2 = 9.47 vs. CRF 1 -mediated cAMP production in Y79 cells). BMS-763534 accelerated the dissociation of 125 I-o-CRF from rat frontal cortex membrane CRF 1 receptors consistent with a negative allosteric modulation of CRF binding. BMS-763534 produced dose-dependent increases in CRF 1 receptor occupancy and anxiolytic efficacy; lowest effective anxiolytic dose = 0.56 mg/kg, PO, which was associated with 71 ± 5% CRF 1 receptor occupancy of frontoparietal CRF 1 receptors. Sedative/ataxic effects of BMS-763534 were only observed at high dose multiples (54–179×) relative to the lowest dose required for anxiolytic efficacy. At doses of 5- to 18-fold higher than the lowest efficacious dose in the anxiety assay, BMS-763534 shared subjective effects with the benzodiazepine chlordiazepoxide. Interestingly BMS-790318, the O-demethylated metabolite of BMS-763534, showed weak affinity for the TBOB site of the GABA A receptor (67% inhibition at 10 μM) and augmented GABA evoked currents (EC 50  = 1.6 μM). Thus, the unanticipated signal in the drug discrimination assay may have resulted from an interaction of the metabolite BMS-790318 with the TBOB site on the GABA A channel where it appears to behave as an allosteric potentiator of GABA evoked currents.