Monoamine oxidase isoform-dependent tautomeric influence in the recognition of 3,5-diaryl pyrazole inhibitors.

Monoamine oxidases (MAO, EC 1.4.3.4), widely distributed in all living organisms, are FAD-containing enzymes, tightly bound to the outer mitochondrial membrane. In mammals, two different isoforms of MAOs are present, namely, MAO-A and MAO-B. MAO-A is located predominantly in catecholaminergic neurons, while MAO-B is present in serotonergic neurons and glia. Both isoforms are characterized by specific substrates and inhibitors. MAO-A has a higher affinity for serotonin and norepinephrine and is more sensitive to inhibition by clorgyline, while MAO-B preferentially deaminates â-phenylethylamines and benzylamine and is sensitive to low concentrations of L-deprenyl.3,4 Dopamine, tyramine, and tryptamine are common substrates for both MAOs. MAO-A inhibitors retain antidepressant effects in animal models and are devoid of the severe food and drug incompatibilities induced by the first generation of MAO inhibitors; MAO-B inhibitors are also currently used in clinical trials in the treatment of Alzheimer’s disease because an increased level of MAO-B has been detected in the plaque-associated astrocytes of brains from Alzheimer’s patients.A series of 3,5-diaryl pyrazoles were prepared and assayed for their ability to inhibit reversibly monoamine oxidase-A (MAO-A) and monoamine oxidase B (MAO-B). Several compounds show inhibitory activity with concentration values in the nanomolar range. A computational work was carried out on the two most selective inhibitors that have tautomeric pyrazole forms. The binding free energies of these compounds for each MAO isoform were influenced by the tautomeric equilibri