RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 293
OP 302
DO 10.1124/jpet.103.058784
VO 309
IS 1
A1 Snjezana Lelas
A1 Harvey Wong
A1 Yu-Wen Li
A1 Karen L. Heman
A1 Kathryn A. Ward
A1 Kim L. Zeller
A1 Kristine K. Sieracki
A1 Joseph L. Polino
A1 Helen E. Godonis
A1 Shelly X. Ren
A1 Xiao-Xin Yan
A1 Stephen P. Arneric
A1 David W. Robertson
A1 Paul R. Hartig
A1 Scott Grossman
A1 George L. Trainor
A1 Rebecca A. Taub
A1 Robert Zaczek
A1 Paul J. Gilligan
A1 John F. McElroy
YR 2004
UL http://jpet.aspetjournals.org/content/309/1/293.abstract
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