Janssen P A, Niemegeers C J, Awouters F, Schellekens K H, Megens A A, Meert T F
Department of Pharmacology, Janssen Research Foundation, Beerse, Belgium.
J Pharmacol Exp Ther. 1988 Feb;244(2):685-93.
Comparative studies of the benzisoxazole derivative risperidone (R 64 766) were made with ritanserin, a selective centrally acting serotonin-S2 antagonist and with haloperidol, a selective centrally acting dopamine-D2 antagonist. Risperidone like ritanserin shows activity in all tests related to serotonin-S2 antagonism, but at even lower doses (peripheral S2-antagonism at 0.0011 mg/kg, central S2-antagonism at 0.014 mg/kg). Like haloperidol, risperidone shows activity in all tests related to dopamine-D2 antagonism; activity in rats for both compounds starts at 0.016 mg/kg, but some central nervous system controlled functions, including the induction of catalepsy, are relatively much less affected by risperidone. Qualitatively, risperidone is a mixed serotonin-dopamine antagonist. Quantitatively, its study in dogs reveals potent dopamine-D2 antagonistic activity with excellent p.o. bioavailability and a relatively long duration of action. From the obtained pharmacological data, risperidone could be expected to possess the complementary clinical effects of a ritanserin-like serotonin-S2 and an haloperidol-like dopamine-D2 antagonist. Serotonin-S2 antagonism may improve the quality of sleep, reduce negative and affective symptoms in schizophrenic patients and decrease extrapyramidal symptoms induced by classical neuroleptics. Because risperidone is a dopamine-D2 antagonist, antidelusional, antihallucinatory and antimanic actions are expected. The first clinical studies indicate that two additional therapeutic targets, which are not reached with classical neuroleptics, may be obtained with risperidone in the monotherapy of schizophrenia and related disorders: very important contact and mood-elevating properties and extrapyramidal symptoms-free maintenance therapy.
对苯并异恶唑衍生物利培酮（R 64 766）进行了比较研究，将其与选择性中枢作用的5-羟色胺-S2拮抗剂利坦色林以及选择性中枢作用的多巴胺-D2拮抗剂氟哌啶醇进行比较。利培酮与利坦色林一样，在所有与5-羟色胺-S2拮抗作用相关的试验中均显示出活性，但剂量更低（外周S2拮抗作用为0.0011mg/kg，中枢S2拮抗作用为0.014mg/kg）。与氟哌啶醇一样，利培酮在所有与多巴胺-D2拮抗作用相关的试验中均显示出活性；两种化合物在大鼠中的活性均从0.016mg/kg开始，但利培酮对包括僵住症诱导在内的一些中枢神经系统控制的功能影响相对较小。从性质上讲，利培酮是一种5-羟色胺-多巴胺混合拮抗剂。从数量上讲，其在犬类中的研究显示出强效的多巴胺-D2拮抗活性，口服生物利用度极佳且作用持续时间相对较长。根据所获得的药理学数据，预计利培酮具有类似利坦色林的5-羟色胺-S2和类似氟哌啶醇的多巴胺-D2拮抗剂的互补临床效果。5-羟色胺-S2拮抗作用可能改善睡眠质量、减轻精神分裂症患者的阴性和情感症状，并减少经典抗精神病药物引起的锥体外系症状。由于利培酮是一种多巴胺-D2拮抗剂，预计具有抗妄想、抗幻觉和抗躁狂作用。首批临床研究表明，在精神分裂症及相关疾病的单药治疗中，利培酮可能实现两个经典抗精神病药物无法达到的额外治疗靶点：非常重要的接触和情绪提升特性以及无锥体外系症状的维持治疗。
