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.

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.

• Authors: N Aubin, P Barneoud, C Carter, D Caille, N Sontag, C Marc, J Lolivier, A Gardes, C Perron, A Le Kim, T Charieras, M Pandini, P Burnier, F Puech, S Jegham, P George, B Scatton, O Curet
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 310 Issue 3 Pg. 1171-82 (Sep 2004) ISSN: 0022-3565 [Print] United States
• PMID: 15178694 (Publication Type: Journal Article)

Chemical References

• 3-methoxymethyl-7-(4,4,4-trifluorobutoxy)-3,3a,4,5-tetrahydro-1,3-oxazolo(3,4-a)quinolin-1-one
• Benzophenones
• Monoamine Oxidase Inhibitors
• Nitrophenols
• Oxazoles
• Quinolines
• 3,4-Dihydroxyphenylacetic Acid
• Serotonin
• Levodopa
• Oxidopamine
• Tolcapone
• Monoamine Oxidase
• Dopamine
• Tyramine

Topics

• 3,4-Dihydroxyphenylacetic Acid (metabolism)
• Animals
• Benzophenones (pharmacology)
• Brain (drug effects, enzymology)
• Corpus Striatum (drug effects, metabolism)
• Disease Models, Animal
• Dopamine (metabolism)
• Drug Interactions
• Levodopa
• MPTP Poisoning (metabolism)
• Maze Learning (drug effects)
• Mice
• Mice, Inbred C57BL
• Monoamine Oxidase (metabolism)
• Monoamine Oxidase Inhibitors (pharmacology, therapeutic use)
• Nervous System Diseases (chemically induced, drug therapy, metabolism)
• Nitrophenols
• Oxazoles (pharmacology, therapeutic use)
• Oxidopamine
• Prefrontal Cortex (drug effects, metabolism)
• Quinolines (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Serotonin (metabolism)
• Stereotyped Behavior (drug effects)
• Tolcapone
• Tremor (chemically induced, drug therapy)
• Tyramine (pharmacology)