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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >S33138 (N-(4-(2-((3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro(1) benzopyrano(3,4-c)pyrrol-2(3H)-yl)-ethyl)phenyl-acetamide), a preferential dopamine D3 versus D2 receptor antagonist and potential antipsychotic agent: III. Actions in models of therapeutic a
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S33138 (N-(4-(2-((3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro(1) benzopyrano(3,4-c)pyrrol-2(3H)-yl)-ethyl)phenyl-acetamide), a preferential dopamine D3 versus D2 receptor antagonist and potential antipsychotic agent: III. Actions in models of therapeutic a

机译：S33138（N-（4-（2-（（（3aS，9bR）-8-氰基-1,3a，4,9b-四氢（1）苯并吡喃基（3,4-c）吡咯-2（3H）-基）） -乙基）苯基乙酰胺），相对于D2受体拮抗剂的优先多巴胺D3和潜在的抗精神病药：III。治疗性A模型的作用

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摘要

In contrast to clinically available antipsychotics, the novel benzopyranopyrrolidine derivative, S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H) -yl)-ethyl]phenyl-acetamide), behaves as a preferential antagonist of D(3) versus D(2) receptors and does not interact with histamine H(1) and muscarinic receptors. In contrast to haloperidol, clozapine, olanzapine, and risperidone, S33138 (0.16-2.5 mg/kg s.c.) did not disrupt performance in passive-avoidance and five-choice serial reaction time procedures. Furthermore, upon either systemic administration (0.04-2.5 mg/kg s.c.) or introduction into the frontal cortex (0.04-0.63 mug/side), S33138 potently attenuated the perturbation of social recognition by scopolamine or a prolonged intersession delay. Over a comparable and low-dose range, S33138 (0.04-0.63 mg/kg s.c.) elevated dialysis levels of acetylcholine in the frontal cortex of freely moving rats. At higher doses (2.5-10.0 mg/kg s.c.), S33138 also increased frontocortical levels of histamine, whereas monoamines, glutamate, glycine, and GABA were unaffected. By analogy to the other antipsychotics, S33138 (0.63-10.0 mg/kg s.c.) inhibited conditioned avoidance responses in rats, apomorphine-induced climbing in mice, and hyperlocomotion elicited by amphetamine, cocaine, dizocilpine, ketamine, and phencyclidine in rats. S33138 (0.16-2.5 mg/kg s.c.) also blocked the reduction of prepulse inhibition elicited by apomorphine. In comparison with the above actions, only "high" doses of S33138 (10.0-40.0 mg/kg s.c.) elicited catalepsy. To summarize, reflecting preferential blockade of D(3) versus D(2) receptors, S33138 preserves and/or enhances cognitive function, increases frontocortical cholinergic transmission, and is active in models of antipsychotic properties at doses well below those inducing catalepsy. In comparison with clinically available agents, S33138 displays, thus, a distinctive and promising profile of potential antipsychotic properties.
机译：与临床上可用的抗精神病药相反，新型苯并吡喃吡咯烷衍生物S33138（N- [4- [2-[（3aS，9bR）-8-cyano-1,3a，4,9b-四氢[1]苯并吡喃[3,4 -c]吡咯-2（3H）-基）-乙基]苯基-乙酰胺），表现为D（3）对D（2）受体的优先拮抗剂，并且不与组胺H（1）和毒蕈碱受体相互作用。与氟哌啶醇，氯氮平，奥氮平和利培酮相反，S33138（0.16-2.5 mg / kg s.c.）不会破坏被动回避和五选择式连续反应时间程序的性能。此外，在全身性给药（0.04-2.5 mg / kg s.c.）或引入额叶皮层（0.04-0.63杯/侧面）时，S33138均可有效减轻东pol碱对社会认可的干扰或延长的休会时间。在相当的低剂量范围内，S33138（0.04-0.63 mg / kg s.c.）提高了自由活动大鼠额叶皮质中乙酰胆碱的透析水平。在较高剂量（2.5-10.0 mg / kg s.c.）下，S33138还增加了额叶皮质醇的组胺水平，而单胺，谷氨酸，甘氨酸和GABA则不受影响。与其他抗精神病药类似，S33138（0.63-10.0 mg / kg s.c.）抑制大鼠的条件回避反应，阿扑吗啡诱导的小鼠爬升以及苯丙胺，可卡因，地佐西平，氯胺酮和苯环利定引起的运动过度。 S33138（0.16-2.5 mg / kg s.c.）也阻止了阿扑吗啡引起的前脉冲抑制作用的降低。与上述作用相比，仅“高”剂量的S33138（10.0-40.0 mg / kg s.c.）引起僵直。总而言之，反映了D（3）与D（2）受体的优先阻断作用，S33138保留和/或增强了认知功能，增加了额叶胆碱能传导，并且在抗精神病特性模型中的剂量远低于诱导僵直的剂量。与临床上可获得的药剂相比，S33138因此显示出潜在的抗精神病药物特性的独特和有希望的概况。

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