Matsui A, Matsuo H, Takanaga H, Sasaki S, Maeda M, Sawada Y
Faculty of Pharmaceutical Sciences, Kyushu University, Higashiku, Fukuoka 812-8582, Japan.
J Pharmacol Exp Ther. 1998 Nov;287(2):725-32.
Recently, clinical cases of parkinsonism due to antiarrhythmics drugs amiodarone and aprindine and a local anesthetic drug procaine have been reported. We performed both in vivo and in vitro experiments to quantitatively predict the intensity of catalepsy by these drugs and haloperidol in mice. Haloperidol showed the most potent relative intensity of catalepsy, followed by aprindine, metoclopramide, tiapride, amiodarone and procaine, in that order. In vivo dopamine D1 and D2 receptor occupancies of the six drugs to the striatum were observed. In vitro binding affinity (Ki) of these drugs to the D1 and D2 receptors in the striatum synaptic membrane was within the range of 60 nM to 706 microM, 0.5 nM to 75 microM and 860 nM to 115 microM, respectively. A good correlation between the relative intensity of drug-induced catalepsy and the Ki values for the dopamine D1 and D2 receptors was obtained (r =.911 and r =.896, respectively; P <.05). The partial tertiary structure of the tested drugs was well superimposed on that of haloperidol. In conclusion, these drug-induced catalepsies were due to the blockade of the D1 and D2 receptors, which was related to the analogous tertiary structures (diethylaminoethyl side chain).
最近，已有因抗心律失常药物胺碘酮和安搏律定以及局部麻醉药普鲁卡因导致帕金森综合征的临床病例报道。我们进行了体内和体外实验，以定量预测这些药物和氟哌啶醇在小鼠中引起僵住症的强度。氟哌啶醇引起僵住症的相对强度最高，其次依次是安搏律定、甲氧氯普胺、硫必利、胺碘酮和普鲁卡因。观察了这六种药物对纹状体的体内多巴胺D1和D2受体占有率。这些药物对纹状体突触膜中D1和D2受体的体外结合亲和力（Ki）分别在60 nM至706 microM、0.5 nM至75 microM和860 nM至115 microM范围内。药物诱导的僵住症相对强度与多巴胺D1和D2受体的Ki值之间存在良好的相关性（r分别为0.911和0.896；P <.05）。受试药物的部分三级结构与氟哌啶醇的三级结构很好地重叠。总之，这些药物诱导的僵住症是由于D1和D2受体的阻断，这与类似的三级结构（二乙氨基乙基侧链）有关。
