Subject(s)
Appetite Depressants/pharmacology , Amphetamine/antagonists & inhibitors , Amphetamine/pharmacology , Animals , Appetite Depressants/classification , Dogs , Dopamine Antagonists , Fenfluramine/antagonists & inhibitors , Fenfluramine/pharmacology , Hydroxydopamines/pharmacology , Metergoline/pharmacology , Methysergide/pharmacology , Mice , Norepinephrine/antagonists & inhibitors , Raphe Nuclei/drug effects , Rats , Serotonin Antagonists/pharmacologyABSTRACT
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.
Subject(s)
Antipsychotic Agents/chemical synthesis , Cyproheptadine/analogs & derivatives , Animals , Avoidance Learning/drug effects , Cyproheptadine/chemical synthesis , Cyproheptadine/pharmacology , Drug Interactions , Haplorhini , Humans , Magnetic Resonance Spectroscopy , Parasympatholytics/chemical synthesis , Parasympatholytics/pharmacology , Saimiri , Stereoisomerism , Stereotyped Behavior/drug effectsABSTRACT
BE-2254, 2-[beta-(4-hydroxyphenyl)-ethylaminomethyl]-tetralone, (ED50 = 3.4 mg/kg i.p.) was about equal to chlorpromazine (ED50 = 4.4) as an antagonist of central noradrenergic receptor stimulation produced by clonidine (enhancement of the flexor reflex in spinalized rats). Haloperidol and phentolamine had essentially no effect at 9 mg/kg i.p...
