Chlorpromazie and Dopamine: Conformational Similarities that Correlate with the Antischizophrenic Activity of Phenothiazine Drugs

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Abstract
Phenothiazines and butyrophenones are known to alter dopamine (3,4-dihydroxyphenethylamine) metabolism in the brain in a fashion suggesting that they may block dopamine receptors. We observed, using Dreiding molecular models, that dopamine in its solid-state conformation is superimposable upon a portion of the known x-ray structure of chlorpromazine [2-chloro-10-(3-dimethylaminopropyl)-phenothiazine]. The ability of phenothiazine drugs to mimic the dopamine-like conformation correlates with their antischizophrenic efficacy. These structure-activity relationships explain the importance of a substituent in ring a , a three-carbon side chain bearing the amino group, and a hetero atom between rings a and c .