SL25.1131 [3(S),3a(S)-3-Methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1,3-oxazolo[3,4-a]quinolin-1-one],a New,Reversible,and Mixed Inhibitor of Monoamine Oxidase-A and Monoamine Oxidase-B:Biochemical and Behavioral Profile

摘要

SL25.1131 [3(S),3a(S)-3-methoxymethyl-7-[4,4,4-trifluorobu-toxy]-3,3a,4,5-tetrahydro-1,3-oxazolo[3,4-a]quinolin-1 -one] is a new,nonselective,and reversible monoamine oxidase (MAO) inhibitor,belonging to a oxazoloquinolinone series.In vitro studies showed that SL25.1131 inhibits rat brain MAO-A and MAO-B with IC_(50) values of 6.7 and 16.8 nM and substrate-dependent K_1 values of 3.3 and 4.2 nM,respectively.In ex vivo conditions,the oral administration of SL25.1131 induced a dose-dependent inhibition of MAO-A and MAO-B activities in the rat brain with ED_(50) values of 0.67 and 0.52 mg/kg,respectively.In the rat brain,duodenum,and liver,the inhibition of MAO-A and MAO-B by SL25.1131 (3.5 mg/kg p.o.) was reversible,and the recovery of MAO-A and MAO-B activities was complete 16 h after administration.SL25.1131 (3.5 mg/kg p.o.) increased tissue levels of dopamine (DA),norepinephrine,and 5-hydroxytryptamine and decreased levels of their deaminated metabolites 3,4-dihydroxyphenylacetic acid,homovanillic acid,and 5-hydroxyindolacetic acid.In mice,SL25.1131 induced a dose-dependent potentiation of 5-hydroxytryptophan-induced tremors and phenylethylamine-induced stereotypies with ED_(50) values of 0.60 and 2.8 mg/kg p.o.,respectively.SL25.1131 was able to reestablish normal striatal dopaminergic tone and locomo-tor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-le-sioned mice.In addition,when coadministered with L-DOPA,SL25.1131 increased the available DA in the striatum and the duration of L-DOPA-induced hyperactivity.The duration of the effect of L-DOPA on circling behavior in 6-hydroxydopamine-le-sioned rats was also increased.The neurochemical profile of SL25.1131 demonstrates that this compound is a mixed,potent,and reversible MAO-A/B inhibitor in vitro,in vivo,and ex vivo.SL25.1131 has therapeutic potential as a symptomatic treatment during the early phase of Parkinson's disease and as an adjunct to L-DOPA therapy during the early and late phases of the disease.