A reversible monoamine oxidase inhibitor, toloxatone: comparison of its physicochemical properties with those of other inhibitors including brofaromine, harmine, R40519 and moclobemide

Reversible, competitive and selective monoamine oxidase A inhibitors (MAOAIs) are an exciting new type of anti-depressants with a safe profile. The mechanism for reversible inhibition of MAOA at the molecular level is still unknown. The planar structure of most reversible MAOAIs and the well-defined acceptor power of flavin adenine dinucleotide (FAD), the cofactor of the enzyme, suggest that MAOAIs exert their inhibitory effect through charge-transfer interactions with the FAD. This hypothesis has been evaluated for Toloxatone 1, the first reversible MAO-AI marketed in France. In this work, we give evidence for the ability of other reversible MAOAIs, including Brofaromine 2, Harmine 3 and R40519 4 to interact with the flavin cofactor in comparison with Moclobemide 5, and we underline the physicochemical properties required for these interactions. First, the formation of a complex between each of the MAOAIs and riboflavin, a model of the flavin cofactor, is shown by electronic absorption spectroscopy. Essential electronic describers of MAOAIs, such as the molecular electrostatic potential and the topology of the frontier orbitals, are then calculated by the ab initio Hartree-Fock method and compared with those of previously studied Toloxatone. This confirms the electronic absorption spectroscopy results. Finally, the similarities between the different MAOAIs are underlined and an interaction model is discussed on the basis of a detailed analysis of the electronic describers of all the considered MAOAIs and the flavin nucleus. (authors). 49 refs., 14 figs., 3 tabs