Inhibition of MAO by β-Carbolinium Halides

Abstract

In the search for a compound capable of selective inhibition of peripheral MAO, a number of 2,9-disubstkuted β-carbolinium compounds were synthesized. With tryptamine as the substrate, these compounds generally exerted greater inhibition of the enzyme from human liver mitochondria than that from bovine liver. An exception to this was 2-propargyl-9-methyl-β-carbolinium bromide (VII), which inhibited the enzyme from both sources to a nearly equal extent. The inhibitory activity of 2,9-dimethyl-β-carbolinium iodide (I) was further studied with mitochondrial MAO of human liver, heart, and brain; rat liver, heart, and brain; mouse liver; and bovine liver; tryptamine and tyramine were used as substrates. Compound I was more effective than pargyline in inhibiting tryptamine oxidation by human MAO from peripheral tissues but was less active than pargyline toward tyramine oxidation. Kinetic studies on the inhibition of tryptamine oxidation indicated I to be a mixed-type inhibitor with MAO from human tissues and rat liver and competitive with MAO from rat heart and brain and bovine liver. The inactivation of tryptamine oxidation by I was reversible in nature, as was VII which bears a propargyl (CH2C ≡ CH) group, the same group that endows pargyline with its irreversible binding to MAO. Since the rate of irreversible inactivation of MAO by pargyline was decreased by the presence of I, there exists the possibility of a common binding site for the two compounds.