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.
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.
Aubin
N
N
CNS Research Department, SANOFI-Synthélabo Recherche, 31 avenue Paul-Vaillant Couturier, 92220 Bagneux, France.
Barneoud
P
P
Carter
C
C
Caille
D
D
Sontag
N
N
Marc
C
C
Lolivier
J
J
Gardes
A
A
Perron
C
C
Le Kim
A
A
Charieras
T
T
Pandini
M
M
Burnier
P
P
Puech
F
F
Jegham
S
S
George
P
P
Scatton
B
B
Curet
O
O
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D007980:Levodopa; D020267:MPTP Poisoning / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D009422:Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D009596:Nitrophenols; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D016627:Oxidopamine; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects; D000077867:Tolcapone; D014202:Tremor / Q000139:chemically induced / Q000188:drug therapy; D014439:Tyramine / Q000494:pharmacology
C492672:3-methoxymethyl-7-(4,4,4-trifluorobutoxy)-3,3a,4,5-tetrahydro-1,3-oxazolo(3,4-a)quinolin-1-one; D001577:Benzophenones; D008996:Monoamine Oxidase Inhibitors; D009596:Nitrophenols; D010080:Oxazoles; D011804:Quinolines; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D007980:Levodopa; D016627:Oxidopamine; D000077867:Tolcapone; D008995:Monoamine Oxidase; D004298:Dopamine; D014439:Tyramine