STERIC REQUIREMENTS FOR CATECHOLAMINE UPTAKE BY RAT BRAIN SYNAPTOSOMES: STUDIES WITH RIGID ANALOGS OF AMPHETAMINE

¹ Department of Pharmacology and Experimental Therapeutics and Psychiatry and the Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland

The effects of cis- and trans-2-phenylcyclopropylamine and 1- and 2-amino-indanes, all rigid analogs of amphetamine, were examined for their ability to inhibit catecholamine uptake into synaptosomes from the hypothalamus and corpus striatum. trans-2-Phenylcyclopropylamine (tranylcypromine) was found to be a more potent inhibitor in both brain areas than the cis-isomer. Studies on the separate optical isomers of tranylcypromine showed that the (-)-isomer was more active than the (+)-form in both the hypothalamus and corpus striatum. 2-Aminoindane was a better inhibitor than 1-aminoindane in both regions of the brain. The above results suggest that the conformation of amphetamine at the catecholamine uptake site is with the side chain fully extended and the amino group above the plane of the ring. i.e., in an anti conformation. It is also suggested that knowledge of the differential antidepressant efficacy of (+)- and (-)-tranylcypromine might indicate the extent to which the drug's antidepressant activity is related to inhibition of monoamine oxidase activity or to impairment of catecholamine reuptake.

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