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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 243; no. 1; pp. 110 - 117
• Main Authors: A E Jacobson, E A Harrison, Jr, M V Mattson, M F Rafferty, K C Rice, J H Woods, G Winger, R E Solomon, R A Lessor, J V Silverton
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.10.1987
• Subjects: Analgesics - pharmacology; Animals; Biological and medical sciences; Brain - metabolism; Dioxolanes - administration & dosage; Dioxolanes - metabolism; Dioxolanes - pharmacology; Dioxoles - pharmacology; Discrimination (Psychology) - drug effects; Isomerism; Ketamine - pharmacology; Kinetics; Macaca mulatta; Medical sciences; Models, Molecular; Molecular Conformation; Neuropharmacology; Pharmacology. Drug treatments; Phencyclidine - metabolism; Piperidines - administration & dosage; Piperidines - metabolism; Piperidines - pharmacology; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Receptors, Neurotransmitter - drug effects; Receptors, Neurotransmitter - metabolism; Receptors, Phencyclidine; Self Administration; Stereoisomerism; Structure-Activity Relationship; Stereoselectivity; Vertebrata; Biological fixation; Mammalia; Animal; Monkey; Primates; Antidepressant agent; Stimulus discrimination; Isomer; Biological receptor
• ISSN: 0022-3565; 1521-0103

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.