利培酮与新型和参比抗精神病药物的体外和体内受体结合比较。
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Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE
利培酮与新型和参比抗精神病药物的体外和体内受体结合比较。
精神药理学(Berl)。1996年3月,124(2):57 - 73。
- PubMed ID
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8935801 (PubMed视图］
- 摘要
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将利培酮及其活性代谢物9- oh利培酮与参考抗精神病药物(氟哌啶醇、哌潘龙、氟替匹林、氯氮平、左替平)和正在开发的化合物(奥氮平、思瑞康、舍替乐、org5222、Ziprasidone)在体外与脑组织和表达克隆人类受体的重组细胞膜上的神经递质受体结合，并在急性治疗后在大鼠和豚鼠大脑中占据神经递质受体(2小时，s.c)。采用离体放射自显影技术测定体内药物对受体的占用。特别令人感兴趣的是中枢5HT2A受体和d2型受体。主要的5HT2A受体拮抗作用被认为增加了抗精神病药物的非典型特征(治疗阴性症状，锥体外系副作用发生率低)。D2拮抗剂需要治疗阳性症状。新的多巴胺受体亚型D3，特别是D4受体的贡献已被提出。在体外，除了“典型的”抗精神病药物氟哌啶醇和氟平匹林外，所有化合物对5HT2A的亲和力都高于对D2受体的亲和力。ORG-5222、sertindole、利培酮、9- oh -利培酮和齐拉西酮对人5HT2A受体具有亚纳摩尔亲和力。氟哌啶酮、ORG-5222、氟哌啶醇、齐拉西酮、利培酮、9- oh利培酮和佐替平对人D2受体表现出纳米摩尔亲和力。 Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D2 affinity in vitro. Clozapine, but even more so pipamperone, displayed higher affinity for D4 than for D2 receptors. For most other compounds, D4 affinity was only slightly lower than their D2 affinity. Seroquel was totally devoid of D4 affinity. None of the compounds had nanomolar affinity for D1 receptors; their affinity for D3 receptors was usually slightly lower than for D2 receptors. In vivo, ORG-5222, risperidone, pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT2A than D2 receptors. Risperidone and ORG-5222 had 5HT2A versus D2 potency ratio of about 20. Highest potency for 5HT2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT2A receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D2 receptors. No regional selectivity for D2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic alpha 1 receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more alpha 1 than D2 receptors. Clozapine showed predominant occupancy of H1 receptors and occupied cholinergic receptors with equivalent potency to D2 receptors. A stronger predominance of 5HT2A versus D2 receptor occupancy combined with a more gradual occupancy of D2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT2A and D2 occupancy and the avoidance of D2 receptor overblockade are believed to reduce the risk for extrapyra
引用这篇文章的药物银行数据
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药物 目标 种类 生物 药理作用 行动 Fluspirilene 5-羟色胺受体2A 蛋白质 人类 未知的拮抗剂细节 Fluspirilene 多巴胺D2受体 蛋白质 人类 是的拮抗剂细节 Pipamperone 5-羟色胺受体2A 蛋白质 人类 未知的受体激动剂细节 Pipamperone α -1肾上腺素能受体(蛋白组) 蛋白质组 人类 未知的拮抗剂细节 Pipamperone - 2a肾上腺素能受体 蛋白质 人类 未知的拮抗剂细节 Pipamperone 多巴胺D2受体 蛋白质 人类 未知的拮抗剂细节 Pipamperone 多巴胺D4受体 蛋白质 人类 未知的拮抗剂细节 - 绑定属性
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药物 目标 财产 测量 pH值 温度(°C) 阿司咪唑 组胺H1受体 Ki (nM) 0.8 N/A N/A 细节 氯氮平 5-羟色胺受体 Ki (nM) 140 N/A N/A 细节 氯氮平 5-羟色胺受体1B Ki (nM) 390 N/A N/A 细节 氯氮平 5-羟色胺受体 Ki (nM) 580 N/A N/A 细节 氯氮平 5-羟色胺受体1E Ki (nM) 430 N/A N/A 细节 氯氮平 5-羟色胺受体2A Ki (nM) 9.6 N/A N/A 细节 氯氮平 - 2a肾上腺素能受体 Ki (nM) 50 N/A N/A 细节 氯氮平 - 2b肾上腺素能受体 Ki (nM) 22 N/A N/A 细节 氯氮平 α - 2c肾上腺素能受体 Ki (nM) 9.1 N/A N/A 细节 氯氮平 组胺H1受体 Ki (nM) 0.23 N/A N/A 细节 Fluspirilene 5-羟色胺受体2A Ki (nM) 9.5 N/A N/A 细节 氟哌啶醇 5-羟色胺受体2A Ki (nM) 200 N/A N/A 细节 丙咪嗪 钠依赖性血清素转运体 Ki (nM) 0．15 N/A N/A 细节 奥氮平 5-羟色胺受体2A Ki (nM) 2.5 N/A N/A 细节 奥氮平 组胺H1受体 Ki (nM) 0.65 N/A N/A 细节 Oxymetazoline - 2a肾上腺素能受体 Ki (nM) 1.3 N/A N/A 细节 Paliperidone 5-羟色胺受体 Ki (nM) 590 N/A N/A 细节 Paliperidone 5-羟色胺受体 Ki (nM) 170 N/A N/A 细节 Paliperidone 5-羟色胺受体2A Ki (nM) 1 N/A N/A 细节 Paliperidone - 2a肾上腺素能受体 Ki (nM) 30. N/A N/A 细节 Paliperidone - 2b肾上腺素能受体 Ki (nM) 9.4 N/A N/A 细节 Paliperidone α - 2c肾上腺素能受体 Ki (nM) 11 N/A N/A 细节 Paliperidone 组胺H1受体 Ki (nM) 32 N/A N/A 细节 普萘洛尔 -1肾上腺素能受体 Ki (nM) 0．02 N/A N/A 细节 喹硫平 5-羟色胺受体 Ki (nM) 320 N/A N/A 细节 喹硫平 5-羟色胺受体1B Ki (nM) 2050 N/A N/A 细节 喹硫平 5-羟色胺受体 Ki (nM) 5000 N/A N/A 细节 喹硫平 5-羟色胺受体1E Ki (nM) 1250 N/A N/A 细节 喹硫平 5-羟色胺受体2A Ki (nM) 96 N/A N/A 细节 喹硫平 - 2a肾上腺素能受体 Ki (nM) 2230 N/A N/A 细节 喹硫平 - 2b肾上腺素能受体 Ki (nM) 90 N/A N/A 细节 喹硫平 α - 2c肾上腺素能受体 Ki (nM) 350 N/A N/A 细节 喹硫平 组胺H1受体 Ki (nM) 2.2 N/A N/A 细节 Sertindole 5-羟色胺受体2A Ki (nM) 0.39 N/A N/A 细节 舒马曲坦 5-羟色胺受体1B Ki (nM) 1.2 N/A N/A 细节 舒马曲坦 5-羟色胺受体 Ki (nM) 1.7 N/A N/A 细节 齐拉西酮 5-羟色胺受体 Ki (nM) 12 N/A N/A 细节 齐拉西酮 5-羟色胺受体1B Ki (nM) 0.99 N/A N/A 细节 齐拉西酮 5-羟色胺受体 Ki (nM) 5.1 N/A N/A 细节 齐拉西酮 5-羟色胺受体1E Ki (nM) 360 N/A N/A 细节 齐拉西酮 5-羟色胺受体2A Ki (nM) 1.4 N/A N/A 细节 齐拉西酮 - 2a肾上腺素能受体 Ki (nM) 160 N/A N/A 细节 齐拉西酮 - 2b肾上腺素能受体 Ki (nM) 48 N/A N/A 细节 齐拉西酮 α - 2c肾上腺素能受体 Ki (nM) 77 N/A N/A 细节 齐拉西酮 组胺H1受体 Ki (nM) 15 N/A N/A 细节 - 药物的相互作用Learn More" title="" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
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