Development of the strategy for the quantitative prediction and avoidance of drug-induced Parkinsonism based on pharmacokinetics and pharmacodynamics

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i) The intensity of catalepsy and in vivo receptor occupancies for domapine D1, D2 and muscarinic acetylcholine receptors were investigated for 25 drugs in mice. The intensity of catalepsy was found to be predictable from these receptor occupancies.ii) The relationship between structure and drug-induced parkinsonism was investigated. The diethylaminomethyl moiety was found to play an important role in the induction of parkinsonism.iii) A case of propiverine-induced parkinsonism was found. The mechanisms underlying the induction of parkinsonism by propiverine was investigated in mice.iv) In vitro experiments were carried out to estimate the affinities of 25 drugs for dopamine D1, D2 and muscarinic acetylcholine receptors, which were indispensable for quantitative prediction of drug-induced parkinsonism.v) Developed was the strategy for the quantitative prediction of drug-induced parkinsonism in humans using the above results of i) and iv).vi) The above(iv) strategy was applied to develop a computer-aided drug information system for rational prescription.