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

Neuropharmacology. 2013 Apr:67:284-93. doi: 10.1016/j.neuropharm.2012.10.025. Epub 2012 Nov 19.

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.

MeSH terms

  • Aminopyridines / chemistry
  • Aminopyridines / metabolism
  • Aminopyridines / pharmacology*
  • Animals
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Humans
  • Male
  • Motor Activity / drug effects*
  • Motor Activity / physiology*
  • Protein Binding / physiology
  • Pyrazines / chemistry
  • Pyrazines / metabolism
  • Pyrazines / pharmacology*
  • Rats
  • Rats, Inbred SHR
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
  • Receptors, Corticotropin-Releasing Hormone / metabolism*
  • Sheep
  • Swine

Substances

  • Aminopyridines
  • BMS-763534
  • Pyrazines
  • Receptors, Corticotropin-Releasing Hormone
  • CRF receptor type 1