Inhibition of monoamine oxidases A and B by simple isoquinoline alkaloids: racemic and optically active 1,2,3,4-tetrahydro-, 3,4-dihydro-, and fully aromatic isoquinolines

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Abstract
A series of 1,2,3,4-tetrahydro,3,4,-dihydro-, and fully aromatic isoquinolines were tested as substrates and/or inactivators of highly purified human monoamine oxidase A and B (MAO A and B). None were found to be a substrate for either enzyme, but many of these isoquinolines could selectively inhibit either MAO A or B. Stereoselective competitive inhibition of MAO A was found with the R enantiomer of all the stereoisomers tested, including salsolinol (Ki = 31 .mu.M), salsoline (Ki - 77 .mu.M), salsolidine (Ki = 6 .mu.M), and carnegine (Ki = 2 .mu.M). As a class, the 3,4-dihydroisoquinolines were the most potent inhibitors tested (Ki = 2-130 .mu.M), and the fully aromatic isoquinolines had intermediate activity (Ki = 17-130 .mu.M) against MAO A. In contrast, only a few of these compounds markedly inhibited MAO B. 1,2,3,4-Tetrahydroisoquinoline, its 2-methyl derivative, and o-methylcorypalline gave apparent Ki values of 15,1 and 29 .mu.M , respectively, and two 3,4-dihydroisoquinolines (compounds 22 and 25) showed substantial inhibition of MAO B (Ki = 76 and 15 .mu.M, respectively). These results support the concept that the topography of the inhibitor binding site differs in MAO A and B.