The evaluation of N-propargylamine-2-aminotetralin as an inhibitor of monoamine oxidase

Abstract

Monoamine oxidase B (MAO-B) inhibitors are established therapy for Parkinson’s disease and act, in part, by blocking the MAO-catalysed metabolism of dopamine in the brain. Two propargylamine-containing MAO-B inhibitors, selegiline [(R)-deprenyl] and rasagiline, are currently used in the clinic for this purpose. These compounds are mechanism-based inactivators and, after oxidative activation, form covalent adducts with the FAD co-factor. An important consideration is that selegiline and rasagiline display specificity for MAO-B over the MAO-A isoform thus reducing the risk of tyramine-induced changes in blood-pressure. In the interest of discovering new propargylamine MAO inhibitors, the present study synthesises racemic N-propargylamine-2-aminotetralin (2-PAT), a compound that may be considered as both a six-membered ring analogue of rasagiline and a semi-rigid N-desmethyl ring-closed analogue of selegiline. The in vitro human MAO inhibition properties of this compound were measured and the results showed that 2-PAT is a 20-fold more potent inhibitor of MAO-A (IC50 = 0.721 µM) compared to MAO-B (IC50 = 14.6 µM). Interestingly, dialysis studies found that 2-PAT is a reversible MAO-A inhibitor, while acting as an inactivator of MAO-B. Since reversible MAO-A inhibitors are much less liable to potentiate tyramine-induced side effects than MAO-A inactivators, it is reasonable to suggest that 2-PAT could be a useful and safe therapeutic agent for disorders such as Parkinson’s disease and depression.