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BEHAVIORAL PHARMACOLOGY

Anxiolytic-Like Effects of the Corticotropin-Releasing Factor₁ (CRF₁) Antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] Administered Acutely or Chronically at Doses Occupying Central CRF₁ Receptors in Rats

Neuroscience Biology (S.L., Y.-W.L., K.L.H., K.A.W., K.L.Z., K.K.S., J.L.P., H.E.G., X.-X.Y., S.P.A., D.W.R., P.R.H., R.A.T., R.Z., J.F.M.), Metabolism and Pharmacokinetics Discovery (H.W., S.X.R., S.G.), and Discovery Chemistry (G.L.T., P.J.G.), Bristol-Myers Squibb Company, Wallingford, Connecticut

Corticotropin-releasing factor₁ (CRF₁) antagonists may be effective in the treatment of anxiety disorders with fewer side effects compared with classic benzodiazepines. The behavioral effects of DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] and its effects on the hypothalamic-pituitary-adrenal (HPA) axis were related to its levels in plasma and estimated occupancy of central CRF₁ receptors. DMP904 (10-30 mg/kg, p.o.) and alprazolam (10 mg/kg, p.o.) increased time spent in open arms of an elevated-plus maze. In addition, acutely or chronically (14 days) administered DMP904 (1.0-30 mg/kg, p.o.) and acute alprazolam (1.0-3.0 mg/kg, p.o.) significantly reduced exit latency in the defensive withdrawal model of anxiety in rats, suggesting that tolerance may not develop to the anxiolytic-like effects of DMP904 in this model of anxiety. Acutely, DMP904 reversed the stress-induced increase in plasma corticosterone levels in defensive withdrawal at doses of 3.0 mg/kg and higher. These doses also resulted in levels of DMP904 in plasma similar to (for anxiolytic-like effects) or 4-fold higher (for effects on the HPA axis) than the in vitro IC₅₀ value for binding affinity at CRF₁ receptors and greater than 50% occupancy of CRF₁ receptors. Unlike alprazolam, DMP904 did not produce sedation, ataxia, or chlordiazepoxide-like subjective effects (as measured by locomotor activity, rotorod performance, and chlordiazepoxide discrimination assays, respectively) at doses at least 3-fold higher than anxiolytic-like doses. In conclusion, anxiolytic-like effects and effects on the stress-activated HPA axis of DMP904 in the defensive withdrawal model of anxiety required 50% or greater occupancy of central CRF₁ receptors. This level of CRF₁ receptor occupancy resulted in fewer motoric side effects compared with classic benzodiazepines.

Address correspondence to: Dr. Snjezana Lelas, Bristol-Myers Squibb Company, P.O. Box 5100, 5 Research Parkway, Wallingford, CT 06492. E-mail: snjezana.lelas{at}bms.com

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