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. 1975 May;72(5):1899–1903. doi: 10.1073/pnas.72.5.1899

Phenothiazine drugs: structure-activity relationships explained by a conformation that mimics dopamine.

A P Feinberg, S H Snyder
PMCID: PMC432655  PMID: 239403

Abstract

The antischizophrenic activity of phenothiazine drugs and their tendency to elicit extrapyramidal symptoms are thought to involve blockade of synaptic dopamine receptors in the brain. Space filling molecular models show how favorable Van der Waal's interactions between the side chain amino of phenothiazines and the 2-substituent on ring A can promote a conformation mimicking dopamine. These Van der Waal's attractive forces can expain (i) the greater potency of drugs with trifluoromethyl rather than chlorine as a 2-substituent; (ii) the enhanced activity of phenothiazines with piperazine instead of alkylamino side chains; (iii) the increased potency associated with hydroxyethylpiperazines as contrasted to piperazine side chains; (iv) the greater potency of cis rather than trans thioxanthenes; and (v) the crucial location of the ring A substituent at carbon no. 2. Potential energy calculations support the observations with molecular models and suggest an active conformation for the phenothiazines.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

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