Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B

1 Rasagiline [N-propargyl-1R(+)-aminoindan], was examined for its monoamine oxidase (MAO) A and B inhibitor activities in rats together with its S(-)-enantiomer (TVP 1022) and the racemic compound (AGN-1135) and compared to selegiline (I-deprenyl). The tissues that were studied for MAO inhibition were the brain, liver and small intestine. 2 While rasagiline and AGN1135 are highly potent selective irreversible inhibitors of MAO in vitro and in vivo. the S(-) enantiomer is relatively inactive in the tissues examined. 3 The in vitro IC50 values for inhibition of rat brain MAO activity by rasagiline are 4.43 +/- 0.92 nM (type B), and 412 +/- 123 nM (type A). The ED50 values for ex vivo inhibition of MAO in the brain and liver by a single dose of rasagiline are 0.1 +/- 0.01, 0.042 +/- 0.0045 mg kg(-1) respectively for MAO-B, and 6.48 +/- 0.81, 2.38 +/- 0.35 mg kg(-1) respectively for MAO-A. 4 Selective MAO-B inhibition in the liver and brain was maintained on chronic (21 days) oral dosage with ED50 values of 0.014 +/- 0.002 and 0.013 +/- 0.001 mg kg(-1) respectively. 5 The degree of selectivity of rasagiline for inhibition of MAO-B as opposed to MAO-A was similar to that of selegiline. Rasagiline was three to 15 times more potent than selegiline for inhibition of MAO-B in rat brain and liver in vivo on acute and chronic administration, but had similar potency in vitro. 6 These data together with lack of tyramine sympathomimetic potentiation by rasagiline, at selective MAO-B inhibitory dosage, indicate that this inhibitor like selegiline may be a useful agent in the treatment of Parkinson's disease in either symptomatic or L-DOPA adjunct therapy, but lack of amphetamine-like metabolites could present a therapeutic advantage for rasagiline.