Enantiomeric and diastereomeric dioxadrols: behavioral, biochemical and chemical determination of the configuration necessary for phencyclidine-like properties.
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.
Jacobson
A E
AE
Laboratory of Neuroscience, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.
Harrison
E A
EA
Mattson
M V
MV
Rafferty
M F
MF
Rice
K C
KC
Woods
J H
JH
Winger
G
G
Solomon
R E
RE
Lessor
R A
RA
Silverton
J V
JV
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004148:Dioxolanes / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D004149:Dioxoles / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects; D007536:Isomerism; D007649:Ketamine / Q000494:pharmacology; D007700:Kinetics; D008253:Macaca mulatta; D008958:Models, Molecular; D008968:Molecular Conformation; D010622:Phencyclidine / Q000378:metabolism; D010880:Piperidines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D017478:Receptors, Phencyclidine; D012646:Self Administration; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000700:Analgesics; D004148:Dioxolanes; D004149:Dioxoles; D010880:Piperidines; D017981:Receptors, Neurotransmitter; D017478:Receptors, Phencyclidine; C005840:dioxadrol; D007649:Ketamine; C579649:levoxadrol; D010622:Phencyclidine; C579650:dexoxadrol