TY - JOUR T1 - Anxiolytic-Like Effects of the Corticotropin-Releasing Factor<sub>1</sub> (CRF<sub>1</sub>) Antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-<em>a</em>]-pyrimidine] Administered Acutely or Chronically at Doses Occupying Central CRF<sub>1</sub> Receptors in Rats JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 293 LP - 302 DO - 10.1124/jpet.103.058784 VL - 309 IS - 1 AU - Snjezana Lelas AU - Harvey Wong AU - Yu-Wen Li AU - Karen L. Heman AU - Kathryn A. Ward AU - Kim L. Zeller AU - Kristine K. Sieracki AU - Joseph L. Polino AU - Helen E. Godonis AU - Shelly X. Ren AU - Xiao-Xin Yan AU - Stephen P. Arneric AU - David W. Robertson AU - Paul R. Hartig AU - Scott Grossman AU - George L. Trainor AU - Rebecca A. Taub AU - Robert Zaczek AU - Paul J. Gilligan AU - John F. McElroy Y1 - 2004/04/01 UR - http://jpet.aspetjournals.org/content/309/1/293.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -