Vol. 287, Issue 2, 725-732, November 1998

Prediction of Catalepsies Induced by Amiodarone, Aprindine and Procaine: Similarity in Conformation of Diethylaminoethyl Side Chain¹

Akiko Matsui, Hirotami Matsuo, Hitomi Takanaga, Shigeki Sasaki, Minoru Maeda and Yasufumi Sawada

Faculty of Pharmaceutical Sciences, Kyushu University, Higashiku, Fukuoka 812-8582, Japan

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 (K_i) of these drugs to the D₁ and D₂ receptors in the striatum synaptic membrane was within the range of 60 nM to 706 µM, 0.5 nM to 75 µM and 860 nM to 115 µM, respectively. A good correlation between the relative intensity of drug-induced catalepsy and the K_i 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).