S. Matin, P. Callery, J. Zweig
Aug 1, 1974
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Influential Citations
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Journal
Journal of medicinal chemistry
Abstract
Since an appreciation of the biochemical events associated with psychotomimesis may further our understanding of altered CNS function and mental disease,l a number of studies designed to elucidate the mechanisms of action of psychotomimetic agents have been reported.2 In an effort to explore metabolic parameters which may contribute to the dramatic differences in pharmacological activity observed for structurally similar 1-phenyl-2-aminopropane (amphetamine) derivative^,^-^ we have initiated a program to compare the metabolic fate of selected members of this series. In this paper we report our results on the in uiuo metabolism of the potent psychotomimetic amine l-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane ( l)6v7 in rabbits. As with several 1-phenyl-2-aminopropane derived drugs,8 the pharmacological activities of the (+) and (-) forms of 1 differ, the psychotomimetic activity apparently residing in the (-) isomer.9 Stereoselective metabolic processes are also well documentedlO and in the case of amphetamine have been implicated in the greater CNS stimulant activity of the S enantiomer.11J2 As part of the present study we have examined the stereochemical control factors operating in the in uiuo metabolism of 1 by determining the concentrations of la and lb, the R and S enantiomers of 1, respectively, in the urine of animals treated intraperitoneally with racemic 1. Methods. The enantiomeric composition of urinary 1 was calculated from a knowledge of the ratio of la to lb and the total amount of la and lb present in a particular sample. The ratio of enantiomers was determined by a glpc analysis of the diastereomeric amides 3a and 3b formed by the nonstereoselective condensation of the mixture of la and lb with the chiral acid (S)-(-)-N-pentafluorobenzoylprolyl-1-imidazolide (2) .I3 The total amount of la and lb excreted was estimated by an isotope dilution analysis based on a knowledge of the amount and specific activity of the 14C-labeled 1 administered to the animal and the specific activity of recovered 1 after dilution with a known amount of carrier 1 and purification uia the Nbenzoyl derivative 10.