A COMPARISON OF THE CAPACITIES OF ISOMERS OF AMPHETAMINE, DEOXYPIPRADROL AND METHYLPHENIDATE TO INHIBIT THE UPTAKE OF TRITIATED CATECHOLAMINES INTO RAT CEREBRAL CORTEX SLICES, SYNAPTOSOMAL PREPARATIONS OF RAT CEREBRAL CORTEX, HYPOTHALAMUS AND STRIATUM AND INTO ADRENERGIC NERVES OF RABBIT AORTA

¹ Wellcome Research Laboratories, Research Triangle Park, North Carolina

The uptake of tritiated catecholamines into crude synaptosomal preparations of rat cere bral cortex, hypothalamus and striatum, into rat cerebral cortex slices and into adrenergic nerves of rabbit aorta is inhibited equally by the isomers of amphetamine. In distinction, the uptake of catecholamines into these same preparations is uniformly more sensitive to inhibition by the R-(-) isomer of deoxypipradrol and the 2R:2'R-(+) isomer of methylphenidate than to the S-(+) and 2R: 2'S-(+) Isomers of these compounds, respectively. The data indicate that the receptor sites for all the ``phenethylamine pumps'' studied are similar in not distinguishing between the stereochemical display of a small hydrophobic group at the carbon (the methyl group of amphetamine) and in readily distinguishing between the stereochemical display of a larger hydrophobic group at this carbon, as exemplified by the piperidine ring in deoxypipradrol and methylphenidate. In addition, since the R-(-) isomer of deoxypipradrol is a very potent inhibitor of catecholamine uptake into the striatum, the diphenyl arrangement in this molecule must be readily accepted by the striatal receptor. This high potency of deoxypipradrol contrasts with the low inhibitory potency of tricyclic antidepressants in the striatum. Since the tricyclic molecules are bridged diphenyl compounds, the configuration of the two phenyl groups with respect to each other is relatively fixed whereas in deoxypipradrol the phenyl groups are relatively mobile. The suggestion is made that the receptor in the striatum, in common with the receptors in the other pumps studied, is capable of receiving two phenyl rings but that the position of the two receptive areas for these rings, with respect to each other, is different in the stniatum than it is in those Pumps in which the tricyclic antidepressants are potent inhibitors of catecholamine uptake.

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