Synthesis, absolute configuration, and molecular modeling study of etoxadrol, a potent phencyclidine-like agonist.
Etoxadrol (2a), one of the eight possible optical isomers of 2-ethyl-2-phenyl-4-(2-piperidyl)-1,3-dioxolane, was synthesized from (S,S)-1-(2-piperidyl)-1,2-ethanediol, which was obtained from cleavage of dexoxadrol (1a, (S,S)-2,2-diphenyl-4-(2-piperidyl)-1,3-dioxolane). The absolute configuration of etoxadrol hydrochloride, a phencyclidine-like compound biologically, was determined to be 2S, 4S, and 6S at its three chiral centers by single-crystal X-ray analysis. Epietoxadrol (2b), epimeric with etoxadrol at the C-2 center, was also obtained from the synthesis. This much less potent enantiomer has the 2R,4S,6S configuration. The affinity of etoxadrol to the phencyclidine binding site was found to be comparable to that of phencyclidine itself and was 35 times more potent than its epimer, epietoxadrol. Three diastereomeric mixtures were prepared that had low affinity for the phencyclidine site. In studies of the discriminative stimulus properties of these compounds, it was found that only etoxadrol substituted for the phencyclidine stimulus. With use of computer-assisted molecular modeling techniques, a hypothetical phencyclidine binding site model has been developed that, unlike our former hypothesis based on Dreiding models, correctly predicts the higher affinity of etoxadrol and the lesser affinity of epietoxadrol for the phencyclidine site.
D000818:Animals; D001522:Behavior, Animal; D001665:Binding Sites / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003198:Computer Simulation; D004148:Dioxolanes / Q000032:analysis / Q000138:chemical synthesis*; D004192:Discrimination, Psychological; D008958:Models, Molecular; D008968:Molecular Conformation; D010622:Phencyclidine / Q000032:analysis / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000138:chemical synthesis*; D051381:Rats; D013237:Stereoisomerism; D014961:X-Ray Diffraction
D004148:Dioxolanes; D010880:Piperidines; D010622:Phencyclidine