Enantiomeric and diastereomeric dioxadrols: Behavioral, biochemical and chemical determination of the configuration necessary for phencyclidine-like properties

A. E. Jacobson, E. A. Harrison, M. V. Mattson, M. F. Rafferty, K. C. Rice, J. H. Woods, G. Winger, R. E. Solomon, R. A. Lessor, J. V. Silverton

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Dioxadrol exists in four isomeric forms, α-(+)-Dioxadrol (dexoxadrol) showed phencyclidine (PCP)-like activity in rhesus monkeys trained to discriminate s.c. administration of ketamine, but neither α-(-)-diaxadrol (levoxadrol) nor β-(±)-dioxadrol showed such activity. In addition, response-contingent i.v. dexoxadrol maintained higher rates of responding than either levoxadrol or β-dioxadrol in monkeys experienced with ketamine self-administration. The order of potency in displacing bound 1-[1-(2-thienyl)cyclohexyl]piperidine from binding sites in rat brain homogenates was dexoxadrol >> levoxadrol = β-(±)-dioxadrol. Viewed in the context of previous studies with stereochemical probes of the PCP receptor, these results extend and confirm the supposition that dexoxadrol and levoxadrol are the stereochemical probes of choice in the study of effects mediated through PCP receptors. The absolute configuration of dexoxadrol was determined to be 4S, 6S by X-ray crystallography, thus defining the optimum chirality necessary for receptor binding and PCP-like activity in the dioxadrol series. Based on these and other considerations, receptor-active conformations of dexoxadrol and PCP are proposed.

Original languageEnglish (US)
Pages (from-to)110-117
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume243
Issue number1
StatePublished - 1987
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Jacobson, A. E., Harrison, E. A., Mattson, M. V., Rafferty, M. F., Rice, K. C., Woods, J. H., Winger, G., Solomon, R. E., Lessor, R. A., & Silverton, J. V. (1987). Enantiomeric and diastereomeric dioxadrols: Behavioral, biochemical and chemical determination of the configuration necessary for phencyclidine-like properties. Journal of Pharmacology and Experimental Therapeutics, 243(1), 110-117.