The CRF(1) receptor antagonist DMP696 produces anxiolytic effects and inhibits the stress-induced hypothalamic-pituitary-adrenal axis activation without sedation or ataxia in rats.
BACKGROUND
CRF(1) antagonists may be effective in the treatment of anxiety disorders while having fewer side effects compared with classical benzodiazepines.


OBJECTIVE
The effects of a small molecule selective CRF(1) antagonist DMP696 on anxiety-like behaviors and stress-induced increases in corticosterone in rats exposed to a novel environment and on locomotor activity and motor coordination were determined in rats. These effects of DMP696 were compared with those produced by the classical benzodiazepine chlordiazepoxide (CDP).


METHODS
DMP696 or CDP were administered PO, 60 minutes before behavioral testing in rats. Their effects on latency to exit a dark chamber and stress-induced increase in corticosterone in the Defensive Withdrawal test (an animal model of anxiety), locomotor activity, and rotorod performance (measure of ataxia) were determined.


RESULTS
DMP696 significantly reduced exit latency and reversed the stress-induced increase in corticosterone in the Defensive Withdrawal test at doses of 3.0-10 mg/kg and higher. In contrast, CDP significantly decreased exit latency at 10 and 30 mg/kg, but not at 100 mg/kg, due to concurrent non-specific side effects. Unlike DMP696, CDP had no effect on the stress-induced increase in corticosterone at lower doses, but resulted in a significant increase at higher doses. DMP696 did not reduce locomotor activity or impair motor coordination at doses up to 30-fold higher than doses effective in the Defensive Withdrawal model. In contrast, CDP produced significant sedation and ataxia at the same doses that were effective in reducing exit latency.


CONCLUSIONS
These data suggest that the CRF(1) antagonist DMP696 might retain the therapeutic benefits of classical benzodiazepines but have fewer motoric side effects.
McElroy
John F
JF
Bristol-Myers Squibb Company, Route 141 and Henry Clay Roads, Experimental Station E400/4414, Wilmington, DE 19880-0400, USA. john.mcelroy@bms.com
Ward
Kathryn A
KA
Zeller
Kim L
KL
Jones
Keith W
KW
Gilligan
Paul J
PJ
He
Liqi
L
Lelas
Snjezana
S
D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy; D001259:Ataxia / Q000209:etiology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002707:Chlordiazepoxide / Q000494:pharmacology; D016292:Procedural Sedation; D003346:Corticotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013312:Stress, Physiological / Q000378:metabolism; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000099052:CRF Receptor, Type 1
D014151:Anti-Anxiety Agents; C404928:DMP 696; D011720:Pyrazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D014227:Triazines; D000099052:CRF Receptor, Type 1; D002707:Chlordiazepoxide; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone