title: 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.affiliation: Bristol-Myers Squibb Company, P.O. Box 5100, 5 Research Parkway, Wallingford, CT 06492, USA. snjezana.lelas@bms.com
authors.forename: Snjezana
authors.initials: S
authors.lastname: Lelas
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
authors.forename: Karen L
authors.initials: KL
authors.lastname: Heman
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Ward
authors.forename: Kim L
authors.initials: KL
authors.lastname: Zeller
authors.forename: Kristine K
authors.initials: KK
authors.lastname: Sieracki
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Polino
authors.forename: Helen E
authors.initials: HE
authors.lastname: Godonis
authors.forename: Shelly X
authors.initials: SX
authors.lastname: Ren
authors.forename: Xiao-Xin
authors.initials: XX
authors.lastname: Yan
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Arneric
authors.forename: David W
authors.initials: DW
authors.lastname: Robertson
authors.forename: Paul R
authors.initials: PR
authors.lastname: Hartig
authors.forename: Scott
authors.initials: S
authors.lastname: Grossman
authors.forename: George L
authors.initials: GL
authors.lastname: Trainor
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Taub
authors.forename: Robert
authors.initials: R
authors.lastname: Zaczek
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Gilligan
authors.forename: John F
authors.initials: JF
authors.lastname: McElroy
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy; D002707:Chlordiazepoxide / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D004193:Discrimination Learning / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D009043:Motor Activity / Q000187:drug effects*; D011720:Pyrazoles / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013375:Substance Withdrawal Syndrome; D000099052:CRF Receptor, Type 1
chemical_list: C417190:4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)pyrazolo(1,5-a)pyrimidine; D014151:Anti-Anxiety Agents; D011720:Pyrazoles; D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D002707:Chlordiazepoxide; D003345:Corticosterone