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

Research output: Contribution to journalArticle

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 explain (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.

Original languageEnglish (US)
Pages (from-to)1899-1903
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume72
Issue number5
DOIs
StatePublished - 1975

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Phenothiazine drugs: structure activity relationships explained by a conformation that mimics dopamine'. Together they form a unique fingerprint.

  • Cite this