ABSTRACT
Six derivatives of 3,3-diphenyl-2-pyrrolidone were synthesized and screened for anticonvulsant activity. The synthetic route involved a mono-N-demethylation of an intermediate N,N-dimethylaminonitrile with methyl chloroformate followed by cleavage of the carbamate group. Of the six derivatives, (+/-)-2-imino-1,5-dimethyl-3,3-diphenylpyrrolidine hydrochloride was effective in protecting mice against maximal electroshock (MES) -induced seizures at a 30-mg/kg dose level.
Subject(s)
Anticonvulsants/chemical synthesis , Pyrrolidinones/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Electroshock , Male , Mice , Nervous System/drug effects , Pentylenetetrazole/antagonists & inhibitors , Pyrrolidinones/pharmacologyABSTRACT
One of the major biotransformation pathways in the metabolism of phencyclidine is hydroxylation at C-4 of the cyclohexane ring to give 4-phenyl-4-(1-piperidinyl)cyclohexanol (1). Since the latter compound can exist as cis and trans isomers and the synthetic mixture has been reported to be biologically active, it was of interest to separate the isomers, test them for biological activity, and determine their ratio as metabolic products of phencyclidine. The synthetic mixture of 1 was separated by TLC and the individual isomers were characterized by 13C and 1H NMR and MS analyses. Preliminary testing of the isomers in the mouse rotarod assay indicates that the trans isomer (1b) is only slightly more active then the cis isomer (1a). Both isomers produced seizure activity and lethality at doses required to produce maximal ataxia.
Subject(s)
Phencyclidine/analogs & derivatives , Phencyclidine/metabolism , Animals , Ataxia/chemically induced , Biotransformation , Dogs , Hydroxylation , Male , Mice , Phencyclidine/toxicity , Seizures/chemically induced , Species Specificity , StereoisomerismABSTRACT
The 13C-NMR spectra reported in these studies give direct evidence for the presence of two contributing conformers for alpha-methadol hydrochloride, alpha-acetylmethadol hydrochloride and beta-acetylmethadol hydrochloride. Indirect evidence is also available for the presence of more than one conformer for beta-methadol hydrochloride. However, in order to be more descriptive about the structures of the conformers, it is necessary to obtain 13C-NMR spectra that have a higher degree of resolution than is available from our present NMR system. Such systems are available, and plans are currently in progress to obtain 13C-NMR spectra or these compounds at high enough magnetic fields and low enough temperatures to give us the necessary data.
