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.

Abstract

Corticotropin-releasing factor(1) (CRF(1)) 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 CRF(1) 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 IC(50) value for binding affinity at CRF(1) receptors and greater than 50% occupancy of CRF(1) 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 CRF(1) receptors. This level of CRF(1) receptor occupancy resulted in fewer motoric side effects compared with classic benzodiazepines.

• Authors: 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, John F McElroy
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 309 Issue 1 Pg. 293-302 (Apr 2004) ISSN: 0022-3565 [Print] United States
• PMID: 14742750 (Publication Type: Journal Article)

Chemical References

• 4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)pyrazolo(1,5-a)pyrimidine
• Anti-Anxiety Agents
• Pyrazoles
• Pyrimidines
• Receptors, Corticotropin-Releasing Hormone
• CRF receptor type 1
• Chlordiazepoxide
• Corticosterone

Topics

• Animals
• Anti-Anxiety Agents (blood, pharmacology, therapeutic use)
• Anxiety (drug therapy)
• Chlordiazepoxide (pharmacology)
• Corticosterone (blood)
• Discrimination Learning (drug effects)
• Male
• Maze Learning (drug effects)
• Motor Activity (drug effects)
• Pyrazoles (blood, pharmacology, therapeutic use)
• Pyrimidines (blood, pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptors, Corticotropin-Releasing Hormone (antagonists & inhibitors)
• Substance Withdrawal Syndrome