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

Abstract

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 (1-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 IC(50) 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 ED(50) 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 ED(50) 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.

Figure 1

Chemical structures of rasagiline, selegiline (deprenyl) and their metabolites.

Figure 2

In vitro inhibitory action of rasagiline and selegiline against rat brain MAO. The test compounds were added to buffer containing 10⁻⁷ M clorgyline (for assay of MAO-B) or 10⁻⁷ M selegiline (for assay of MAO-A) and were incubated with the tissue homogenate for 60 min at pH 7.4 before addition of ¹⁴C-β-phenylethylamine or ¹⁴C-5-hydroxytryptamine respectively.

Figure 3

In vivo MAO inhibitory activity of rasagiline and selegiline in rat brain and liver following a single dose of the compound administered orally. Groups of rats (3 – 5 at each dose level) were injected with the doses of the compounds shown and sacrificed 2 h later. Activity of MAO was determined in a suitably diluted sucrose homogenate of whole brains (minus cerebellum) and liver using ¹⁴C-β-phenylethylamine or ¹⁴C-5-hydroxytryptamine for assay of MAO-B or MAO-A activity respectively. Enzyme activity in tissues from drug-treated animals was expressed as a percentage of the enzyme activity in tissues of animals treated with normal saline. Mean values shown±s.e.mean.

Figure 4

In vivo MAO inhibitory activity of rasagiline and selegiline in rat brain and liver following chronic treatment with the compounds p.o. Groups of rats (4 – 6 at each dose level) were treated daily by gavage with the doses of the compounds shown for 21 days and sacrificed 24 h after the last dose. Activity of MAO was determined in suitable dilutions of a sucrose homogenate of whole brain (minus cerebellum) or liver using ¹⁴C-β-phenylethylamine or ¹⁴C-5-hydroxytryptamine for assay of MAO-B or MAO-A activity respectively. Enzyme activity in drug-treated rats is expressed as a percentage of the enzyme activity in brain or liver tissue of control animals treated with normal saline. Mean values shown±s.e.mean.