Inhibition of monoamine oxidase selectively in brain monoamine nerves using the bioprecursor (E)-beta-fluoromethylene-m-tyrosine (MDL 72394), a substrate for aromatic L-amino acid decarboxylase

Abstract

(E)-beta-Fluoromethylene-m-tyrosine (FMMT) is a dual-enzyme-activated inhibitor of monoamine oxidase (MAO). The compound is not an inhibitor per se but is decarboxylated by aromatic L-amino acid decarboxylase (AADC) to yield a potent enzyme-activated irreversible inhibitor of MAO, (E)-beta-fluoromethylene-m-tyramine, which shows some selectivity for inhibition of MAO type A. Decarboxylation of FMMT was demonstrated in vitro using hog kidney AADC and in vivo in rats by the ability of alpha-monofluoromethyldopa (MFMD), a potent inhibitor of AADC, to prevent MAO inhibition produced by FMMT. In isolated synaptosomes, FMMT was decarboxylated by AADC, and, furthermore, the compound was actively transported into these isolated nerve endings. An active transport into the CNS has also been demonstrated in vivo by performing competition experiments with leucine. To demonstrate that FMMT is preferentially decarboxylated within monoamine nerves of the CNS, the nigrostriatal 3,4-dihydroxyphenylethylamine (dopamine) pathway of rats was unilaterally lesioned with 6-hydroxydopamine or infused with MFMD. Under these conditions, MAO inhibition produced by orally administered FMMT in the striatum ipsilateral to the lesion or infusion was markedly attenuated. Combination of FMMT with an inhibitor of extracerebral AADC, such as carbidopa, protected peripheral organs against the MAO inhibitory effects and concomitantly enhanced MAO inhibition in the CNS. Such combinations had a greatly reduced propensity to augment the cardiovascular effects of intraduodenally administered tyramine, when compared with FMMT given alone or with clorgyline, a selective inhibitor of MAO type A. The results obtained with FMMT suggest the possibility of achieving selective inhibition of MAO within monoamine nerves of the CNS and, further, suggest that combination of FMMT with an inhibitor of extracerebral AADC will reduce the propensity of this inhibitor to produce adverse interactions with tyramine.