Simiand J, Keane P E, Barnouin M C, Keane M, Soubrié P, Le Fur G
Sanofi Recherche, Toulouse, France.
Fundam Clin Pharmacol. 1993;7(8):413-27.
The effect of the 5-HT1A agonist SR 57746A (1-[2-(naphth-2-yl) ethyl]-4-(3-trifluoromethylphenyl))-1,2,5,6 tetrahydropyridine hydrochloride), was evaluated in a variety of psychopharmacological tests in rodents. In the approach-avoidance conflict test in rats, orally administered SR 57746A significantly increased punished responding at doses as low as 3 mg/kg, while unpunished responding was only reduced at 30 mg/kg. SR 57746A was active for at least 4 hours in this test. SR 57746A significantly antagonised the lithium-induced taste aversion in rats at doses of 3 and 10 mg/kg po. In staircase test in mice, SR 57746A reduced rearing at doses which did not reduce the number of steps climbed. In the two-compartment exploratory model in mice, SR 57746A increased the latency to the first entry into the dark compartment (at 2 to 8 mg/kg po), and reduced the time spent in the dark compartment (at 8 mg/kg po), but had no effect on the total number of transitions. SR 57746A potently reduced aggressive behaviour in isolated mice, the dose of 1 mg/kg po produced over 80% inhibition of fighting in this test. SR 57746A was also active in the behavioural despair test of depression in mice and rats, and reversed learned helpless behaviour in rats. SR 57746A was also active in the behavioural despair test of depression in mice and rats, and reversed learned helpless behaviour in rats. SR 57746A dose-dependently generalised to the cue produced by 8-OH-DPAT in rats, but produced only a very weak serotonergic syndrome. Like 8-OH-DPAT and ipsapirone, SR 57746A reduced body temperature in mice, but only at a high dose (10 mg/kg po). SR 57746A reversed haloperidol-induced catalepsy in rats with an ED50 of 3.85 mg/kg po, but was unable to antagonise the stereotypy induced by apomorphine in this species. SR 57746A was inactive or only very weakly active in a series of tests typical of benzodiazepine-like activity, including antagonism of pentetrazol-induced seizures, reduction of muscle tone and locomotor activity, impairment of motor co-ordination, and potentiation of the effects of centrally-acting sedative-hypnotics. SR 57746A was also inactive as an analgesic in the PBQ writhing test. Thus, SR 57746A is active in a number of tests indicative of 5-HT1A receptor stimulation in vivo, and, more particularly, in a number of tests predictive of anxiolytic, anti-aggressive and antidepressant activities. SR 57746A is as potent as diazepam in anxiolytic tests, and more potent than imipramine in antidepressant tests, whereas it is devoid of neuroleptic potential. In view of this profile of activity, SR 57746A merits evaluation as a potential anxiolytic and antidepressant in humans.
在啮齿动物的多种精神药理学试验中评估了5-羟色胺1A（5-HT1A）激动剂SR 57746A（1-[2-(萘-2-基)乙基]-4-(3-三氟甲基苯基)-1,2,5,6-四氢吡啶盐酸盐）的作用。在大鼠的趋避冲突试验中，口服给予SR 57746A，低至3mg/kg的剂量就能显著增加受罚反应，而只有在30mg/kg时未受罚反应才会减少。在该试验中，SR 57746A的活性至少持续4小时。SR 57746A以3mg/kg和10mg/kg的口服剂量能显著拮抗大鼠中锂诱导的味觉厌恶。在小鼠的阶梯试验中，SR 57746A在不减少攀爬步数的剂量下降低了竖毛次数。在小鼠的两室探索模型中，SR 57746A增加了首次进入暗室的潜伏期（口服剂量为2至8mg/kg），并减少了在暗室中停留的时间（口服剂量为8mg/kg），但对总转换次数没有影响。SR 57746A能有效降低隔离小鼠的攻击行为，在该试验中，1mg/kg的口服剂量能产生超过80%的打斗抑制。SR 57746A在小鼠和大鼠的行为绝望抑郁试验中也有活性，并逆转了大鼠的习得性无助行为。SR 57746A在小鼠和大鼠的行为绝望抑郁试验中也有活性，并逆转了大鼠的习得性无助行为。SR 57746A在大鼠中对8-OH-DPAT产生的线索呈剂量依赖性泛化，但仅产生非常微弱的5-羟色胺能综合征。与8-OH-DPAT和伊沙匹隆一样，SR 57746A能降低小鼠体温，但仅在高剂量（10mg/kg口服）时有效。SR 57746A能逆转氟哌啶醇诱导的大鼠僵住症，口服半数有效剂量（ED50）为3.85mg/kg，但在该物种中无法拮抗阿扑吗啡诱导的刻板行为。SR 57746A在一系列典型的苯二氮䓬样活性试验中无活性或只有非常微弱的活性，包括拮抗戊四氮诱导的惊厥、降低肌张力和运动活性、损害运动协调性以及增强中枢作用的镇静催眠药的效果。SR 57746A在苯醌扭体试验中作为镇痛药也无活性。因此，SR 57746A在许多表明体内5-HT1A受体受刺激的试验中具有活性，更具体地说，在许多预测抗焦虑、抗攻击和抗抑郁活性的试验中具有活性。在抗焦虑试验中，SR 57746A与地西泮效力相当，在抗抑郁试验中比丙咪嗪效力更强，而它没有抗精神病药的潜力。鉴于这种活性特征，SR 57746A值得作为一种潜在的抗焦虑和抗抑郁药物在人体中进行评估。
