STEREOSELECTIVITY OF CATECHOLAMINE UPTAKE BY BRAIN SYNAPTOSOMES: STUDIES WITH EPHEDRINE, METHYLPHENIDATE AND PHENYL-2-PIPERIDYL CARBINOL

¹ Departments of Pharmacology and Experimental Therapeutics and Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland; Division of Medicinal Chemistry, The Ohio state University, College of Pharmacy, Columbus, Ohio

In this study we examined the stereoselectivity of catecholamine uptake into synaptosomes prepared from rat cerebral cortex or corpus striatum with isomers of ephedrine, methylphenidate and phenyl-2-piperidyl carbinol, compounds possessing two asymmetric carbons, hence, four possible stereoisomers. The four ephedrine isomers were more potent inhibitors of catecholamine uptake in the cerebral cortex than in the corpus striatum. There was a 100-fold variation in potency among the ephedrine isomers in the cerebral cortex but only a 7-fold variation in the corpus striatum. The optimal configuration at the (S) and (R) carbons (erythro configuration) for activity of the ephedrines in both brain regions corresponds to the configurations of (+)-amphetamine and (-)-norepinephrine, respectively. In contrast, the four phenyl-2-piperidyl carbinol isomers were more potent in the corpus striatum than in the cerebral cortex, and the configuration of the most potent isomer was R at both and carbons, i.e., threo. Also unlike the ephedrines, there was a greater variation in potency among the various phenyl-2-piperidyl carbinol isomers in the striatum than in the cerebral cortex. The methylphenidates, like phenyl-2-piperidyl carbinol, were more potent inhibitors of catecholamine uptake in the corpus striatum than in the cerebral cortex, and the threo racemate of methylphenidate was about 100 times more active than the erythro racemate in both areas. Although ephedrine, amphetamine and norepinephrine isomers show much less stereoselectivity in the corpus striatum than in the cerebral cortex, phenyl-2-piperidyl carbinol and methylphenidate isomers display more stereoselectivity in the corpus striatum than in the cerebral cortex. The relative activity among phenyl-2-piperidyl carbinol and methylphenidate isomers in inhibiting catecholamine uptake is opposite to that of ephedrine isomers.

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