Brain Neurotransmitter Receptor Binding and Neuroleptic Drugs

The molecular mechanism of a therapeutic drug is suggested by the biochemical event that correlates best with clinical potency. Binding is the recognition site of a receptor. The striatal dopamine-sensitive adenylate cyclase, encompasses both a recognition and an effector unit. The neuroleptic drugs exert their therapeutic actions and induce extrapyramidal side effects by blocking the dopamine receptors in the brain. Autonomic sympatholytic effect, such as orthostatic hypotension and sedation, are among the most prominent untoward actions of the neuroleptic drugs. The norepinephrine-sensitive adenylate cyclase in rat limbic forebrain indicates that the neuroleptics have a high affinity for norepinephrine areceptor sites. Stereospecificity and correlations between the clinical and the biochemical effects reveal the biochemical basis of neuroleptic drug action. Droperidol is one-fourth as potent as spiroperidol at the dopamine receptor. There is poor correlation between neuroleptic affinity for H-haloperidol binding sites and norepinephrine and epinephrine toxicity. While molecular modeling indicates how phenothiazines assume the preferred conformation of dopamine, the conformation of butyrophenones at their receptor sites is unclear. In extrapyramidal side effects and muscarinic binding, dopamine receptor blockade in the corpus striatum is responsible for the extrapyramidal side effects of neuroleptic therapy, while dopamine receptor blockade in the limbic forebrain, regions associated with emotional behaviors, is responsible for the antischizophrenic efficacy of the neuroleptic agents.