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 IC 50 values of 6.7 and 16.8 nM and substratedependent K i 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 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.Monoamine oxidase (MAO) deaminates monoamine neurotransmitters as well as exogenous amines. Two isoforms of MAO have been described in mammalian tissue, namely, MAO-A and MAO-B, which exhibit different substrate profiles, respond differently to selective inhibitors, and are present in different cellular and subcellular locations. MAO-A preferentially deaminates 5-hydroxytryptamine (serotonin) (5-HT) and norepinephrine (NE) and is selectively inhibited by clorgyline (Johnston, 1968), whereas MAO-B is selectively inhibited by L-deprenyl and preferentially deaminates phenylethylamine (PEA) and benzylamine (Knoll and Magyar, 1972). Dopamine (DA) and tyramine (TYR) are metabolized by both enzyme isoforms (for review, see StrolinBenedetti and Dostert, 1985).Article, publication date, and citation information can be found at

Pro‐oxidant effects of Ecstasy and its metabolites in mouse brain synaptosomes

“…Based on the results obtained for H 2 O 2 production, the effects of antioxidants and FCCP were evaluated after incubation of synaptosomes with the drugs at a fixed concentration (50 µM). The MAO inhibitors’ concentrations used in this study were selected from previous studies of MAO inhibition (Youdim et al ., 2001; Aubin et al ., 2004). The FCCP concentration used here was selected from studies of maximal mitochondrial depolarization in neurons (Oliveira and Gonçalves, 2009) and synaptosomes (Tretter et al ., 1998).…”

Modification of Monoaminergic Activity by MAO Inhibitors Influences Methamphetamine Actions

“…Selective and non-selective MAO inhibitors have been developed for pre-clinical and clinical purposes, especially as treatments for major depression and Parkinson’s disease (Finberg and Youdim, 1983; Worms et al 1987; Pletscher 1991; Aubin et al 2004). The first MAO inhibitor to be discovered was the hydrazine derivative iproniazid, which was originally developed for the treatment of tuberculosis.…”

“…Aubin et al (2004) reported the behavioral profile of a newly developed, mixed-reversible MAO-A/B inhibitor, SL25.1131, in mice. The agent can improve decreased dopaminergic tone in the striatum by inhibiting MAO-A and –B and locomotion disrupted by treatment with MPTP (1-methyl-4-pheny l–1,2,3,6-tetrahydropyridine).…”

Application of a Cross-Metathesis and Intramolecular Aza-Diels-Alder Sequence to the Synthesis of trans-2,3-Disubstituted Tetrahydroquinolines

“…1,2 Galipinine (1; Figure 1), for example, has been isolated from Galipea officinalis trunk bark and exhibits activity against plasmodium falciparum, the protozoan parasite responsible of malaria; 3 the synthetic compound 2, known as SL 25.1131, is a reversible monoamine oxidase that is structurally related to befloxatone and has shown real therapeutic potential in the early phase of treatment against Parkinson's disease. 4 Virantmycin (3), an antiviral agent, also possesses a highly functionalized tetrahydroquinoline ring. 5…”