Seeger T F, Seymour P A, Schmidt A W, Zorn S H, Schulz D W, Lebel L A, McLean S, Guanowsky V, Howard H R, Lowe J A
Central Research Division, Pfizer Inc., Groton, CT, USA.
J Pharmacol Exp Ther. 1995 Oct;275(1):101-13.
Ziprasidone (CP-88,059) is a combined 5-HT (serotonin) and dopamine receptor antagonist which exhibits potent effects in preclinical assays predictive of antipsychotic activity. Whereas the compound is a dopamine antagonist in vitro and in vivo, its most potent action is antagonism of 5-HT2A receptors, where its affinity is an order of magnitude greater than that observed for dopamine D2 sites. Laboratory and clinical findings have led to a hypothesis that antagonism of 5-HT2A receptors in the brain limits the undesirable motor side effects associated with dopamine receptor blockade and improves efficacy against the negative symptoms of schizophrenia. Ziprasidone possesses an in vitro 5-HT2A/dopamine D2 receptor affinity ratio higher than any clinically available antipsychotic agent. In vivo, ziprasidone antagonizes 5-HT2A receptor-induced head twitch with 6-fold higher potency than for blockade of d-amphetamine-induced hyperactivity, a measure of central dopamine D2 receptor antagonism. Ziprasidone also has high affinity for the 5-HT1A, 5-HT1D and 5-HT2C receptor subtypes, which may further enhance its therapeutic potential. The prediction of antipsychotic efficacy without severe motor side effects is supported by the relatively weak potency of ziprasidone to produce catalepsy in animals, contrasted with its potent antagonism of conditioned avoidance responding and dopamine agonist-induced locomotor activation and stereotypy. The compound is well tolerated in animals at doses producing effective dopamine antagonism in the brain. Ziprasidone should be a valuable addition to the treatment of psychotic disorders.
齐拉西酮（CP - 88,059）是一种5 - 羟色胺（血清素）和多巴胺受体联合拮抗剂，在预测抗精神病活性的临床前试验中显示出强效作用。虽然该化合物在体外和体内均为多巴胺拮抗剂，但其最有效的作用是拮抗5 - HT2A受体，其对该受体的亲和力比多巴胺D2位点高一个数量级。实验室和临床研究结果提出了一种假说，即大脑中5 - HT2A受体的拮抗作用可限制与多巴胺受体阻断相关的不良运动副作用，并提高对精神分裂症阴性症状的疗效。齐拉西酮的体外5 - HT2A/多巴胺D2受体亲和力比值高于任何一种临床可用的抗精神病药物。在体内，齐拉西酮拮抗5 - HT2A受体诱导的头部抽搐的效力比对d - 苯丙胺诱导的多动（一种中枢多巴胺D2受体拮抗作用的指标）的阻断效力高6倍。齐拉西酮对5 - HT1A、5 - HT1D和5 - HT2C受体亚型也具有高亲和力，这可能进一步增强其治疗潜力。与它对条件性回避反应、多巴胺激动剂诱导的运动激活和刻板行为的强效拮抗作用相比，齐拉西酮在动物中产生僵住症的效力相对较弱，这支持了其具有抗精神病疗效而无严重运动副作用的预测。在产生有效脑内多巴胺拮抗作用的剂量下，该化合物在动物中耐受性良好。齐拉西酮应是治疗精神障碍的一种有价值的药物。
