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.ll.charact

摘要

The present study investigated the effects of the novel corticotrophin-relwasing 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 teat battery,and several procedures based on stree-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 teat battery(3-30mg/kg i.p.orp.o.).These effects paralleled those of the anxiolytic diazepan.In addition,SSR125543A and antalarmin antagonized stree-induced hyperthermia,distress vocalization,and cortical norepinephrine release.In the forced swimming test,30mg/kg p.o.SSR125543A and 3 to 30mg/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 10mg/kg i.p.SSR125543A or 30 days improved the degradation of the physical state,the reduction of body weight gain,and anxiety produced by streee.Together,these data indicate that SSR125543A shows good activity in acute and chronic tests of unavoidable stree exposure,suggesting that it may have a potentical in the treatment of depression and some forms of anxiety disorders.