1. 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.
- Author
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Aubin N, Barneoud P, Carter C, Caille D, Sontag N, Marc C, Lolivier J, Gardes A, Perron C, Le Kim A, Charieras T, Pandini M, Burnier P, Puech F, Jegham S, George P, Scatton B, and Curet O
- Subjects
- 3,4-Dihydroxyphenylacetic Acid metabolism, Animals, Benzophenones pharmacology, Brain drug effects, Brain enzymology, Corpus Striatum drug effects, Corpus Striatum metabolism, Disease Models, Animal, Dopamine metabolism, Drug Interactions, Levodopa, MPTP Poisoning metabolism, Mice, Mice, Inbred C57BL, Monoamine Oxidase Inhibitors therapeutic use, Nervous System Diseases chemically induced, Nervous System Diseases drug therapy, Nitrophenols, Oxazoles therapeutic use, Oxidopamine, Prefrontal Cortex drug effects, Prefrontal Cortex metabolism, Quinolines therapeutic use, Rats, Rats, Sprague-Dawley, Serotonin metabolism, Stereotyped Behavior drug effects, Tolcapone, Tremor chemically induced, Tremor drug therapy, Tyramine pharmacology, Maze Learning drug effects, Monoamine Oxidase metabolism, Monoamine Oxidase Inhibitors pharmacology, Nervous System Diseases metabolism, Oxazoles pharmacology, Quinolines pharmacology
- Abstract
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] 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 IC50 values of 6.7 and 16.8 nM and substrate-dependent Ki 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 ED50 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 ED50 values of 0.60 and 2.8 mg/kg p.o., respectively. SL25.1131 was able to reestablish normal striatal dopaminergic tone and locomotor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned 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-lesioned 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.
- Published
- 2004
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