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

BMS-763534 is a potent (CRF1 IC50 = 0.4 nM) and selective (>1000-fold selectivity vs. all other sites tested) CRF1 receptor antagonist (pA2 = 9.47 vs. CRF1-mediated cAMP production in Y79 cells). BMS-763534 accelerated the dissociation of 125I-o-CRF from rat frontal cortex membrane CRF1 receptors consistent with a negative allosteric modulation of CRF binding. BMS-763534 produced dose-dependent increases in CRF1 receptor occupancy and anxiolytic efficacy; lowest effective anxiolytic dose = 0.56 mg/kg, PO, which was associated with 71 ± 5% CRF1 receptor occupancy of frontoparietal CRF1 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 GABAA receptor (67% inhibition at 10 μM) and augmented GABA evoked currents (EC50 = 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 GABAA channel where it appears to behave as an allosteric potentiator of GABA evoked currents.