Janssen P A, Awouters F H
Janssen Research Council, Beerse, Belgium.
Arzneimittelforschung. 1994 Mar;44(3):269-77.
In 1965 the first study of this series reported different effects of neuroleptics in rats, supporting clinical differences. At the one end, haloperidol presented as a potent and specific antagonist of the psychostimulants amphetamine and apomorphine. Haloperidol-like neuroleptics have marked effects on psychomotor agitation, delusions and hallucinations and bind with high affinity to dopamine-D2 receptors. Pipamperone, at the other end, presented with weak "dopamine" antagonism and more striking tryptamine antagonism. Pipamperone is known to improve disturbed sleep, social withdrawal and other symptoms of chronic schizophrenia in the relative absence of extrapyramidal symptoms. These effects have been attributed to central serotonin-S2 antagonism, on the basis of the clinical effects of ritanserin. As shown by the present analysis of relative tryptamine versus apomorphine antagonism of 57 neuroleptics, in comparison to relative S2 vs. D2 binding, there is a continuity in the series. About 30% of the compounds can be considered to act primarily as serotonin antagonists, but few are markedly more potent than pipamperone. In amphetamine-challenged rats pipamperone-like activity is reflected in preferential inhibition of the excessive oxygen consumption rather than of agitation. Risperidone inhibits oxygen consumption (0.016 mg/kg) at the same dose as haloperidol inhibits agitation. Other low-dose effects of risperidone include reversal of amphetamine-induced withdrawal, antagonism of agitation induced by a sequential tryptamine and apomorphine challenge and LSD-antagonism. In dogs, the antiemetic activity of risperidone is characterized by high oral effectiveness which lasts one day and agrees with pharmacokinetic data when allowance is made for the active metabolite 9-hydroxyrisperidone.(ABSTRACT TRUNCATED AT 250 WORDS)
1965年，该系列的第一项研究报告了抗精神病药物在大鼠身上的不同作用，支持了临床差异。一方面，氟哌啶醇表现为精神兴奋剂苯丙胺和阿扑吗啡的强效特异性拮抗剂。氟哌啶醇样抗精神病药物对精神运动性激越、妄想和幻觉有显著作用，并与多巴胺D2受体具有高亲和力结合。另一方面，匹泮哌隆表现出较弱的“多巴胺”拮抗作用和更显著的色胺拮抗作用。已知匹泮哌隆在相对没有锥体外系症状的情况下可改善慢性精神分裂症的睡眠障碍、社交退缩和其他症状。基于利坦色林的临床效果，这些作用被归因于中枢5-羟色胺-S2拮抗作用。正如目前对57种抗精神病药物相对色胺与阿扑吗啡拮抗作用的分析所示，与相对S2与D2结合相比，该系列存在连续性。约30%的化合物可被认为主要作为5-羟色胺拮抗剂起作用，但很少有比匹泮哌隆更有效的。在苯丙胺激发的大鼠中，匹泮哌隆样活性表现为优先抑制过度的氧消耗而非激越。利培酮在与氟哌啶醇抑制激越相同的剂量下抑制氧消耗（0.016mg/kg）。利培酮的其他低剂量作用包括逆转苯丙胺诱导的戒断反应、拮抗色胺和阿扑吗啡序贯激发诱导的激越以及拮抗麦角酸二乙酰胺。在犬类中，利培酮的止吐活性特点是口服有效性高，持续一天，考虑到活性代谢物9-羟利培酮时与药代动力学数据相符。（摘要截短于250字）
