title: 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.
authors.affiliation: Department of Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA. NJL1865@gmail.com
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lodge
authors.forename: Snjezana
authors.initials: S
authors.lastname: Lelas
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
authors.forename: Thaddeus
authors.initials: T
authors.lastname: Molski
authors.forename: James
authors.initials: J
authors.lastname: Grace
authors.forename: Digavalli V
authors.initials: DV
authors.lastname: Sivarao
authors.forename: Debra
authors.initials: D
authors.lastname: Post-Munson
authors.forename: Francine
authors.initials: F
authors.lastname: Healy
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.forename: Richard
authors.initials: R
authors.lastname: Hartz
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.forename: Robert
authors.initials: R
authors.lastname: Zaczek
mesh_terms: D000631:Aminopyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D011719:Pyrazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012756:Sheep; D013552:Swine; D000099052:CRF Receptor, Type 1
chemical_list: D000631:Aminopyridines; C584049:BMS-763534; D011719:Pyrazines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1