Synthesis of Two Nitro Analogs of Tranylcypromine: Relations of Aromatic Substitution of Nitro Groups to MAO-Inhibitory Activity

Two new nitro analogs of tranylcypromine, (E)-2-(p-nitrophenyl)cyclopropylamine ((E)-p-NTCP) and (E)-2-(m-nitrophenyl)cyclopropylamine ((E)-m-NTCP) were synthesized in order to examine the effect of aromatic nitro substitution on the MAO-inhibitory activity of 2-phenylcyclopropylamines. The compounds were obtained by treating t-butyl (E)-2-(p-nitrophenyl) cyclopropanecarbamate and t-butyl (E)-2-(m-nitrophenyl)cyclopropanecarbamate with p-toluenesulfonic acid in $CH_3$CN. Inhibitions of rat brain mitochondrial MAO-A and B by the compounds were examined using serotonin and benzylamine as the substrate at both in vitro and ex vivo levels. It was found from in vitro measurements that (E)-p-NTCP at $6.0{\times}10^{-5}M$ elicited merely 22.5% inhibition against MAO-B without any effect on MAO-A. In contrast, (E)-m-NTCP showed fair degrees of inhibitions of MAO-A and B with $IC_{50}$ values, $2.5{\times}10^{-7}M\;and\;1.4{\times}10^{-6}M$, respectively. It was also noted from (E)-m-NTCP that m-nitro substitution caused a shift of selectivity of the inhibition toward MAO-A. According to ex vivo measurements at 1.5, 3, 6, and 12 hr following the administration of a dose of 0.015 mmol/kg, i.p. to the rats, the inhibition percents of MAO-A by (E)-m-NTCP were 58.6, 63.7 63.6, and 46.6%, slightly lower than those observed by tranylcypromine. Whereas, (E)-m-NTCP at the same dose level did not show significant inhibitions against both MAO-A and MAO-B. Possible reasons for the difference in potencies between (E)-m-NTCP and (E)-p-NTCP were sought in relation to differing electron withdrawing effects of m- and p-substituents which will influence electron density of the side chain amino functions and the partitions.