Antioxidant properties of PF9601N, a novel MAO-B inhibitor: assessment of its ability to interact with reactive nitrogen species.

Abstract

The novel MAO-B inhibitor PF9601N, its cytochrome P450-dependent metabolite FA72 and l-deprenyl were studied as potential peroxynitrite (ONOO(-)) scavengers and nitric oxide synthase (NOS) inhibitors. The scavenging activity of these compounds was evaluated by measuring the oxygen consumption through peroxynitrite-mediated oxidation of both linoleic acid and brain homogenate. FA72, PF9601N and l-deprenyl caused a concentration-dependent inhibition of ONOO(-)-induced linoleic acid oxidation with an IC(50) value of 60.2 microM, 82.8 microM and 235.8 microM, respectively. FA72 was the most potent also in inhibiting ONOO(-)-induced brain homogenate oxidation with an IC(50) value of 99.4 microM, while PF9601N and l-deprenyl resulted weaker inhibitors in the same experimental model, showing an IC(50) value of 164.8 and 112.0 microM, respectively. Furthermore, both the novel MAO-B inhibitor as well as its metabolite were able to strongly inhibit rat brain neuronal NOS (IC(50) of 183 microM and 192 microM, respectively), while l-deprenyl at the highest concentration used (3 mM), caused only a slight decrease of the enzyme activity. Moreover, inducible NOS was strongly inhibited by FA72 only. All these results suggest that PF9601N could be a promising therapeutic agent in neurodegenerative disorders such as Parkinson's disease.