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. Rice, James H Woods, Gail Winger, R. E. Solomon, R. Lessor, J. Silverton
Journal of Pharmacology and Experimental Therapeutics October 1, 1987 DOI: 10.1016/s0022-3565(25)39206-2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Rhesus monkeys trained to discriminate ketamine and experienced with ketamine self-administration; rat brain homogenates for binding assays |
| Interventions | Dexoxadrol Levoxadrol beta-(+/-)-Dioxadrol Ketamine |
| Key findings | Dexoxadrol, but not levoxadrol or beta-dioxadrol, produced phencyclidine-like discriminative stimulus effects and maintained higher rates of intravenous self-administration in ketamine-trained monkeys. Dexoxadrol was far more potent than levoxadrol and beta-dioxadrol at displacing a PCP-site ligand from rat brain binding sites. Its absolute configuration is 4S,6S, which the authors propose defines the chirality required for receptor binding and PCP-like activity. |
Abstract
Dioxadrol exists in four isomeric forms. alpha-(+)-Dioxadrol (dexoxadrol) showed phencyclidine (PCP)-like activity in rhesus monkeys trained to discriminate s.c. administration of ketamine, but neither alpha-(-)-dioxadrol (levoxadrol) nor beta-(+/-)-dioxadrol showed such activity. In addition, response-contingent i.v. dexoxadrol maintained higher rates of responding than either levoxadrol or beta-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 much greater than levoxadrol = beta-(+/-)-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.