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
- Snjezana Lelas,
- Harvey Wong,
- Yu-Wen Li,
- Karen L. Heman,
- Kathryn A. Ward,
- Kim L. Zeller,
- Kristine K. Sieracki,
- Joseph L. Polino,
- Helen E. Godonis,
- Shelly X. Ren,
- Xiao-Xin Yan,
- Stephen P. Arneric,
- David W. Robertson,
- Paul R. Hartig,
- Scott Grossman,
- George L. Trainor,
- Rebecca A. Taub,
- Robert Zaczek,
- Paul J. Gilligan and
- John F. McElroy
- 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
- 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
Abstract
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.
Footnotes
-
DOI: 10.1124/jpet.103.058784.
-
ABBREVIATIONS: CRF, corticotropin-releasing factor; CP-154,526, butyl-ethyl-[2,5-dimethyl-7-(2,4,6,-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine; SSR125543A, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1, 3-thiazol-2-amine hydrochloride; R121919, 3-[6-(dimethylamino)-4-methyl-pyrid-3-yl]-2,5-dimethyl-N,N-dipropyl-pyrazolo[2,3-a]pyrimidin-7-amine; HPA, hypothalamic-pituitary-adrenal; DMP696, 4-(1,3-dimethoxyprop-2-ylamino)-2,7-dimethyl-8-(2,4-dichlorophenyl)-pyrazolo[1,5-a]-1,3,5-triazine; CDP, chlordiazepoxide; DMP904, 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine; LC/MS/MS, liquid chromatography/tandem mass spectometry; FR, fixed ratio.
-
- Received August 18, 2003.
- Accepted December 31, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
