PT - JOURNAL ARTICLE 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 TI - 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 AID - 10.1124/jpet.103.058784 DP - 2004 Apr 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 293--302 VI - 309 IP - 1 4099 - http://jpet.aspetjournals.org/content/309/1/293.short 4100 - http://jpet.aspetjournals.org/content/309/1/293.full SO - J Pharmacol Exp Ther2004 Apr 01; 309 AB - 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