Synthesis and stereospecific antipsychotic activity of (-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine.
The synthesis and resolution of 3-iodocyproheptadine [(+/-)-5a] and 1-cyclopropylmethyl-4-(3-iodo-5H-dibenzo-[a,d]cyclohepten-5-ylidene)piperidine [(+/-)-5b] are described. The resulting atropisomers undergo reaction with trifluoromethylthiocopper to give optically active products without extensive racemization. In this manner, optically pure (+)- and (-)-3-trifluoromethylthiocyproheptadine [(+)-6a and (-)-6a, respectively] and (+)- and (-)-1-cyclopropylmethyl-4-(3-trifluoromethylthio-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine [(+)-6b and (-)-6b, respectively] have been prepared. The influence of a chiral europium shift reagent on the proton and fluorine resonance signals as a diagnostic tool for the determination of the optical purities of these atropisomers is discussed. The four compounds, (+)-6a, (-)-6a, (+)-6b, and (-)-6b, were studied in squirrel monkeys for their ability to block conditioned avoidance responding. All of the antiavoidance activity was found to reside solely in the levorotatory compounds (-)-6a and (-)-6b. Further comparison of the enantiomers (-)-6b and (+)-6b showed that the ability to antagonize apomorphine-induced stereotyped behavior is confined to the levorotatory isomer (-)-6b while weak central anticholinergic activity resides solely in the dextrorotatory isomer (+)-6b. Neither (-)-6b has significant peripheral anticholinergic activity.
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis*; D001362:Avoidance Learning / Q000187:drug effects; D003533:Cyproheptadine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004347:Drug Interactions; D000882:Haplorhini; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010276:Parasympatholytics / Q000138:chemical synthesis / Q000494:pharmacology; D012453:Saimiri; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000187:drug effects
D014150:Antipsychotic Agents; D010276:Parasympatholytics; D003533:Cyproheptadine