Megens A A, Awouters F H, Schotte A, Meert T F, Dugovic C, Niemegeers C J, Leysen J E
Janssen Research Foundation, Beerse, Belgium.
Psychopharmacology (Berl). 1994 Feb;114(1):9-23. doi: 10.1007/BF02245439.
This review reports on the pharmacodynamics of the new antipsychotic risperidone. The primary action of risperidone is serotonin 5-HT2 receptor blockade as shown by displacement of radioligand binding (Ki: 0.16 nM), activity on isolated tissues (EC50: 0.5 nM), and antagonism of peripherally (ED50: 0.0011 mg/kg) and centrally (ED50: 0.014 mg/kg) acting 5-HT2 receptor agonists in rats. Risperidone is at least as potent as the specific 5-HT2 receptor antagonist ritanserin in these tests. Risperidone is also a potent dopamine D2 receptor antagonist as indicated by displacement of radioligand binding (Ki: 1.4 nM), activity in isolated striatal slices (IC50: 0.89 nM), and antagonism of peripherally (ED50: 0.0057 mg/kg in dogs) and centrally acting D2 receptor agonists (ED50: 0.056-0.15 mg/kg in rats). Risperidone shows all effects common to D2 antagonists, including enhancement of prolactin release. However, some central effects such as catalepsy and blockade of motor activity occur at high doses only. Risperidone is 4-10 times less potent than haloperidol as a central D2 antagonist in rats and it differs from haloperidol by the following characteristics: predominant 5-HT2 antagonism; LSD antagonism; effects on sleep; smooth dose-response curves for D2 antagonism; synergism of combined 5-HT2/D2 antagonism; pronounced effects on amphetamine-induced oxygen consumption; increased social interaction; and pronounced effects on dopamine (DA) turnover. Risperidone displays similar activity at pre- and postsynaptic D2 receptors and at D2 receptors from various rat brain regions. The binding affinity for D4 and D3 receptors is 5 and 9 times weaker, respectively, than for D2 receptors; interaction with D1 receptors occurs only at very high concentrations. The pharmacological profile of risperidone includes interaction with histamine H1 and alpha-adrenergic receptors but the compound is devoid of significant interaction with cholinergic and a variety of other types of receptors. Risperidone has excellent oral activity, a rapid onset, and a 24-h duration of action. Its major metabolite, 9-hydroxyrisperidone, closely mimics risperidone in pharmacodynamics. Risperidone can be characterized as a potent D2 antagonist with predominant 5HT2 antagonistic activity and optimal pharmacokinetic properties.
本综述报道了新型抗精神病药物利培酮的药效学。利培酮的主要作用是阻断5-羟色胺（5-HT2）受体，这一作用通过放射性配体结合的置换实验（Ki：0.16 nM）、对离体组织的活性实验（EC50：0.5 nM）以及对大鼠外周（ED50：0.0011 mg/kg）和中枢（ED50：0.014 mg/kg）作用的5-HT2受体激动剂的拮抗作用得以证实。在这些实验中，利培酮至少与特异性5-HT2受体拮抗剂利坦色林一样有效。利培酮也是一种强效的多巴胺D2受体拮抗剂，这可通过放射性配体结合的置换实验（Ki：1.4 nM）、离体纹状体切片中的活性实验（IC50：0.89 nM）以及对外周（犬类的ED50：0.0057 mg/kg）和中枢作用的D2受体激动剂的拮抗作用（大鼠的ED50：0.056 - 0.15 mg/kg）得以表明。利培酮具有D2拮抗剂常见的所有效应，包括催乳素释放增加。然而，一些中枢效应，如僵住症和运动活动的阻断，仅在高剂量时出现。在大鼠中，作为中枢D2拮抗剂，利培酮的效力比氟哌啶醇低4 - 10倍，并且它与氟哌啶醇的不同之处在于以下特征：主要为5-HT2拮抗作用；对麦角酸二乙胺（LSD）的拮抗作用；对睡眠的影响；D2拮抗作用的剂量 - 反应曲线平滑；5-HT2/D2联合拮抗作用的协同效应；对苯丙胺诱导的氧消耗有显著影响；社交互动增加；以及对多巴胺（DA）周转有显著影响。利培酮在突触前和突触后的D2受体以及来自大鼠不同脑区的D2受体上表现出相似的活性。其对D4和D3受体的结合亲和力分别比对D2受体弱5倍和9倍；仅在非常高的浓度下才会与D1受体发生相互作用。利培酮的药理学特性包括与组胺H1和α - 肾上腺素能受体相互作用，但该化合物与胆碱能及多种其他类型的受体无明显相互作用。利培酮具有出色的口服活性、起效迅速且作用持续24小时。其主要代谢产物9 - 羟利培酮在药效学方面与利培酮极为相似。利培酮可被描述为一种强效的D2拮抗剂，具有主要的5HT2拮抗活性以及最佳的药代动力学特性。
