RESUMO
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.
Assuntos
Antipsicóticos/síntese química , Ciproeptadina/análogos & derivados , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Ciproeptadina/síntese química , Ciproeptadina/farmacologia , Interações Medicamentosas , Haplorrinos , Humanos , Espectroscopia de Ressonância Magnética , Parassimpatolíticos/síntese química , Parassimpatolíticos/farmacologia , Saimiri , Estereoisomerismo , Comportamento Estereotipado/efeitos dos fármacosAssuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Tranquilizantes/farmacologia , Tropanos/farmacologia , Animais , Hidrato de Cloral/farmacologia , Clordiazepóxido/farmacologia , Clorpromazina/farmacologia , Clorprotixeno/farmacologia , Eletrochoque , Feminino , Haloperidol/farmacologia , Haplorrinos , Masculino , Meprobamato/farmacologia , Paraldeído/farmacologia , Pentobarbital/farmacologia , Perfenazina/farmacologia , Pupila/efeitos dos fármacos , Reserpina/farmacologia , Tetrabenazina/farmacologia , Tioridazina/farmacologia , Trifluoperazina/farmacologia , Triexifenidil/farmacologiaRESUMO
The behavior of four monkeys trained on a multiple schedule was differentially sensitive to selected pharmacological agents. The three components of the multiple schedule were: (1) a variable-interval schedule in which responses were reinforced on the average of once per minute; (2) a concurrent schedule in which every tenth response was reinforced and every fifteenth response, on the average, was shocked; and, (3) a neutral stimulus in the presence of which responses were neither reinforced nor shocked. Pentobarbital, chlordiazepoxide, and meprobamate increased responding during each of the components. Scopolamine and d-amphetamine decreased variable-interval performance, had minimal effects on performance during the concurrent-schedule component, and increased responding in the presence of the neutral stimulus. Chlorpromazine decreased variable-interval responding and had slight effects on the responding during the other two components.