NOVEL 4-(ARYLOXY)TETRAHYDROPYRIDINE ANALOGS OF MPTP AS MONOAMINE-OXIDASE-A AND MONOAMINE-OXIDASE-B SUBSTRATES

The exceptionally good monoamine oxidase (MAO) substrate properties of several 4-(arylmethyl)-1-methyl-1,2,3,6-tetrahydropyridine derivative s related to the neurotoxin MPTP have prompted studies to evaluate the corresponding properties of tetrahydropyridine derivatives bearing he teroatom-linked groups at C-4. The expected dihydropyridinium metaboli tes generated from these MAO-A- and MAO-B-catalyzed oxidations of the 4-(aryloxy)tetrahydropyridine analogs were found to undergo rapid hydr olytic cleavage to yield the corresponding arenol and 1-methyl-2,3-dih ydro-4-pyridone, a species that could be monitored spectrophotometrica lly. We have exploited this reaction sequence to probe the active site s of beef liver MAO-B and human placental MAO-A with a variety of 4-(a ryloxy)-1-methyl-1,2,3,6-tetrahydropyridine derivatives. The results a re discussed in relationship to recently published reports describing the MAO-A vs MAO-B selectivity of various 4-(arylmethyl)tetrahydropyri dine derivatives.