3H-haloperidol binding to dopamine receptors in rat corpus striatum: Influence of chlorpromazine metabolites and derivatives

Ian Creese, Albert A. Manian, Timothy D. Prosser, Solomon H. Snyder

Research output: Contribution to journalArticle

Abstract

A series of chlorpromazine metabolites and derivatives have been assayed for their ability to compete with 3H-haloperidol binding to dopamine receptors in membranes of rat corpus striatum. 3-Hydroxylation of chlorpromazine doubles affinity for receptor sites, while 7-hydroxychlorpromazine has a potency similar to that of chlorpromazine itself. Other patterns of hydroxylation reduce affinity. Side chain demethylation lowers affinity for binding sites. Several metabolites which lack neuroleptic activity in vivo, such as chlorpromazine-5-oxide, also are inactive in competing for 3H-haloperidol binding. Since blood levels of 7-hydroxychlorpromazine tend to be similar to those of chlorpromazine itself in patients, these observations indicate that 7-hydroxychlorpromazine may account for a major portion of the antischizophrenic efficacy of chlorpromazine. The structure-activity relationship observed in the present study support a model in which chlorpromazine interacts with dopamine receptors by assuming a conformation with its side chain tilted toward ring A.

Original languageEnglish (US)
Pages (from-to)291-296
Number of pages6
JournalEuropean Journal of Pharmacology
Volume47
Issue number3
DOIs
StatePublished - Feb 1 1978

Keywords

  • 7-Hydroxychlorpromazine
  • Chlorpromazine
  • Chlorpromazine metabolites and derivatives
  • Dopamine receptors
  • H-Haloperidol binding

ASJC Scopus subject areas

  • Pharmacology

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