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 (SSR125543A), a potent and selective corticotrophin-releasing factor(1) receptor antagonist. II. Characterization in rodent models of stress-related disorders.
The present study investigated the effects of the novel corticotrophin-releasing factor (CRF)(1) receptor antagonist 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 (SSR125543A) in a variety of rodent models of anxiety, including conflict procedures (punished drinking and four-plate), exploration models (elevated plus-maze and light/dark), a fear/anxiety defense test battery, and several procedures based on stress-induced changes in physiological (isolation-induced hyperthermia and tail pinch-induced cortical norepinephrine release) or behavioral (social defeat-induced anxiety, maternal separation-induced vocalization) parameters. Moreover, the effects of SSR125543A were investigated in acute (forced swimming) and chronic (chronic mild stress; CMS) models of depression. SSR125543A and the CRF(1) receptor antagonist antalarmin displayed limited efficacy in exploration-based anxiety models. In contrast, both compounds produced clear-cut anxiolytic-like activity in models involving inescapable stress, including the conflict procedures, the social defeat-induced anxiety paradigm and the defense test battery (3-30 mg/kg i.p. or p.o.). These effects paralleled those of the anxiolytic diazepam. In addition, SSR125543A and antalarmin antagonized stress-induced hyperthermia, distress vocalization, and cortical norepinephrine release. In the forced swimming test, 30 mg/kg p.o. SSR125543A and 3 to 30 mg/kg p.o. antalarmin produced clear antidepressant-like effects. These latter results were strengthened by the findings from the CMS, which showed that repeated administration of 10 mg/kg i.p. SSR125543A for 30 days improved the degradation of the physical state, the reduction of body weight gain, and anxiety produced by stress. Together, these data indicate that SSR125543A shows good activity in acute and chronic tests of unavoidable stress exposure, suggesting that it may have a potential in the treatment of depression and some forms of anxiety disorders.
Griebel
Guy
G
Central Nervous System Research Department, Sanofi-Synthelabo, Bagneux, France. guy.griebel@sanofi-synthelabo.com
Simiand
Jacques
J
Steinberg
Régis
R
Jung
Mireille
M
Gully
Danielle
D
Roger
Pierre
P
Geslin
Michel
M
Scatton
Bernard
B
Maffrand
Jean-Pierre
JP
Soubrié
Philippe
P
D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003220:Conflict, Psychological; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D007035:Hypothermia / Q000517:prevention & control; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D011678:Punishment; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012934:Social Isolation / Q000523:psychology; D013315:Stress, Psychological / Q000188:drug therapy* / Q000503:physiopathology; D013550:Swimming / Q000523:psychology; D013844:Thiazoles / Q000494:pharmacology*; D014828:Vocalization, Animal / Q000187:drug effects; D000099052:CRF Receptor, Type 1
C451725:4-(2-chloro-4-methoxy-5-methylphenyl)-N(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine; D000928:Antidepressive Agents; D018019:Receptors, Corticotropin-Releasing Hormone; D013844:Thiazoles; D000099052:CRF Receptor, Type 1; D009638:Norepinephrine