A REVERSIBLE MONOAMINE-OXIDASE INHIBITOR TOLOXATONE - COMPARISON OF ITS PHYSICOCHEMICAL PROPERTIES WITH THOSE OF OTHER INHIBITORS INCLUDINGBROFAROMINE, HARMINE, R40519 AND MOCLOBEMIDE

Reversible, competitive and selective monoamine oxidase A inhibitors ( MAO(A)Is) are an exciting new type of anti depressants with a safe pro file. The mechanism for reversible inhibition of MAO(A) at the molecul ar level is still unknown. The planar structure of most reversible MAO (A)Is and the well-defined acceptor power of flavin adenine dinucleoti de (FAD), the cofactor of the enzyme, suggest that MAO Is exert their inhibitory effect through charge-transfer interactions with the FAD. T his hypothesis has been evaluated for Toloxatone 1, the first reversib le MAO(A)I marketed in France. In this work, we give evidence for the ability of other reversible MAO(A)Is, including Brofaromine 2, Harmine 3 and R40519 4 to interact with the flavin cofactor in comparison wit h Moclobemide 5, and we underline the physicochemical properties requi red for these interactions. First, the formation of a complex between each of the MAO(A)Is and riboflavin, a model of the flavin cofactor, i s shown by electronic absorption spectroscopy. Essential electronic de scriptors of MAO(A)Is, such as the molecular electrostatic potential a nd the topology of the frontier orbitals, are then calculated by the a b initio Hartree-Fock method and compared with those of previously stu died Toloxatone. This confirms the electronic absorption spectroscopy results. Finally, the similarities between the different MAO(A)Is are underlined and an interaction model is discussed on the basis of a det ailed analysis of the electronic descriptors of all the considered MAO (A)Is and the flavin nucleus.