Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125 Chemin de Ronde, 78290 Croissy/Seine, France.
J Pharmacol Exp Ther. 2012 Mar;340(3):765-80. doi: 10.1124/jpet.111.187534. Epub 2011 Dec 16.
The present studies characterized the functional profile of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide) (S32212), a combined serotonin (5-HT)(2C) receptor inverse agonist and α(2)-adrenoceptor antagonist that also possesses 5-HT(2A) antagonist properties (J Pharmacol Exp Ther 340:750-764, 2012). Upon parenteral and/or oral administration, dose-dependent (0.63-40.0 mg/kg) actions were observed in diverse procedures. Both acute and subchronic administration of S32212 reduced immobility time in a forced-swim test in rats. Acutely, it also suppressed marble burying and aggressive behavior in mice. Long-term administration of S32212 was associated with rapid (1 week) and sustained (5 weeks) normalization of sucrose intake in rats exposed to chronic mild stress and with elevated levels of mRNA encoding brain-derived neurotrophic factor in hippocampus and amygdala (2 weeks). S32212 accelerated the firing rate of adrenergic perikarya in the locus coeruleus and elevated dialysis levels of noradrenaline in the frontal cortex and hippocampus of freely moving rats. S32212 also elevated the frontocortical levels of dopamine and acetylcholine, whereas 5-HT, amino acids, and histamine were unaffected. These neurochemical actions were paralleled by "promnemonic" properties: blockade of scopolamine-induced deficits in radial maze performance and social recognition and reversal of delay-induced impairments in social recognition, social novelty discrimination, and novel object recognition. It also showed anxiolytic actions in a Vogel conflict procedure. Furthermore, in an electroencephalographic study of sleep architecture, S32212 enhanced slow-wave and rapid eye movement sleep, while decreasing waking. Finally, chronic administration of S32212 neither elevated body weight nor perturbed sexual behavior in male rats. In conclusion, S32212 displays a functional profile consistent with improved mood and cognitive performance, together with satisfactory tolerance.
N-[4-甲氧基-3-(4-甲基哌嗪-1-基)苯基]-1,2-二氢-3-H-苯并[e]吲哚-3-甲酰胺）（S32212）是一种 5-羟色胺（5-HT）（2C）受体反向激动剂和α（2）-肾上腺素能受体拮抗剂，同时具有 5-HT（2A）拮抗剂特性（J Pharmacol Exp Ther 340:750-764, 2012）。在给予 S32212 后，无论是静脉内或口服给药，均观察到剂量依赖性（0.63-40.0mg/kg）的作用。S32212 无论是急性或亚慢性给药，均可减少强迫游泳试验中大鼠的不动时间。急性给药时，它还能抑制小鼠的埋丸和攻击行为。S32212 长期给药与慢性轻度应激大鼠蔗糖摄入的快速（1 周）和持续（5 周）正常化以及海马和杏仁核中脑源性神经营养因子 mRNA 水平升高（2 周）相关。S32212 加速蓝斑核肾上腺素能神经元的放电率，并提高自由活动大鼠前额皮质和海马中的去甲肾上腺素透析水平。S32212 还升高前额皮质的多巴胺和乙酰胆碱水平，而 5-HT、氨基酸和组氨酸不受影响。这些神经化学作用与“记忆增强”特性相平行：阻断东莨菪碱诱导的放射迷宫表现和社会识别缺陷，以及延迟诱导的社会识别、社会新颖性辨别和新物体识别障碍的逆转。它还在 Vogel 冲突程序中显示出抗焦虑作用。此外，在一项脑电图睡眠结构研究中，S32212 增强了慢波和快速眼动睡眠，同时减少了觉醒。最后，S32212 慢性给药既不增加雄性大鼠的体重，也不影响其性行为。总之，S32212 具有改善情绪和认知表现的功能特征，同时具有良好的耐受性。
