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(E) 2-Phenylcyclopropylamine ((E)-TCP), (Z)-2-phenylcyclopropylamine ((Z)-TCP), (E)-1-methyl-2-phenylcyclopropylamine ((E)-MTCP), and (Z)-1-methyl-2-phenylcyclopropylamine ((Z)-MTCP) were synthesized and used to determine to what extent 1-methyl substitution and stereochemistry of 2-phenylcyclopropylamines affect inhibition of monoamine oxidase(MAO). Inhibition of rat brain mitochondrial MAO-A and B by the compounds were measured using serotonin and benzylamine as the substrate, respectively and IC50 values obtained with 95% confidence limits by the method of computation. For the inhibition of MAO-A, (E)-MTCP(IC50 = 6.2 X 10-8M) was found to be 37 times more potent than (Z) MTCP (IC50 = 2.3 X 10-6M), whereas the activity of (E) -TCP (IC50 = 2.9 X 10-7M) was slightly less than that of (Z) -TCP (IC50 = 2.3 X 10-7M). Similarly, for the inhibition of MAO-B, (E) -MTCP (IC50 = 6.3 X 1050 M) was 7 times more potent than (Z) -MTCP (IC50 = 4.7 X 10-7M) and (E)-TCP (IC50 = 7.8 X 10-8M), 0.6 times as potent as (Z) -TCP (IC50 = 4.4 X 10-8M). The results suggested that while without 1-methyl group, potency of a (Z)-isomer was comparable to that of (E) isomer, the methyl group in its (Z) position was very unfavorable to the inhibition of MAO and that in its (E) position, the methyl group contributed positively to the potency as found by the fact that (E) MTCP was 1 5 times more potent than (E)-TCP. In view of the selective inhibition of MAO-A or B, all compounds elicited 4-10 times higher preference for the inhibition of MAO B over MAO A and 1-methyl substitution as well as the stereochemical factors did not significantly influence the selectivity.
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