Modulations of brain amines and dopaminergic behavior by a novel, reversible and selective MAO-B inhibitor

Monoamine oxidase (MAO) B is a validated target for many neurodegenerative diseases. Recently we have reported a few pyrazolines as reversible and selective MAO-B inhibitors. Amongst them, we have selected the most potent analog, NP-9 (Ki=0.31 nM; selectivity index, MAO-B/A more than 100) for the current preclinical study. It selectively inhibited MAO-B activity in liver and brain. Maximum inhibition was observed at 7 mg/kg, i.p., dose, which was reversed after 8h. We did not observe any alteration in amines level on its acute administration, whereas, on its chronic administration we observed significant increase in striatal dopamine level. Other noteworthy observations were (a) it markedly potentiated the 2-phenylethylamine induced stereotype behavior, (b) it partially reversed the reserpine induced oral dyskinesia, (c) it protected the reserpine induced glutathione oxidation (in cerebrum) and (d) no hypertensive crisis was observed on tyramine co-treatment. The study provides a preclinical basis to NP-9 for MAO-B inhibition.