A REVERSIBLE MONOAMINE-OXIDASE INHIBITOR, TOLOXATONE - SPECTROPHOTOMETRIC AND MOLECULAR-ORBITAL STUDIES OF THE INTERACTION WITH FLAVIN ADENINE-DINUCLEOTIDE (FAD)

Toloxatone is a monoamine oxidase A (MAO(A)) inhibitor, marketed as antidepressant devoid of the undesirable side effects of first-generation irreversible monoamine oxidase inhibitors (MAOIs). Its advantages arise from the reversible, competitive and specific nature of its inhibition. The mechanism for irreversible inhibition of MAO(A) at the molecular level is known (suicide substrate). A physicochemical study was undertaken to establish the mechanism of reversible inhibition by Toloxatone. After determination of structural and electronic properties [6], experimental and theoretical approaches were used to explore the possibility of a physical association between the eutomer R-Toloxatone and flavin, a cofactor of MAO(A). For this, 2 models of flavin were used. First, the existence of a charge-transfer complex between R-Toloxatone and riboflavin was demonstrated by electron absorption spectroscopy. Second, ab initio Hartree-Fock calculations of frontier orbitals and electrostatic potentials confirm the favourable overlap of complementary electronic zones of R-Toloxatone and SCH3-lumiflavin for a defined relative orientation.