1-Methyl-2-undecyl-4(1<i>H</i>)-quinolone as an Irreversible and Selective Inhibitor of Type B Monoamine Oxidase

Abstract

Monoamine oxidase (MAO; EC 1.4.3.4) is a flavin-containing enzyme that catalyzes the oxidation of a variety of amine-containing neurotransmitters such as catecholamines and serotonin to yield the corresponding aldehyde. [1][2][3] MAO exists in two isoforms, namely type A and type B (MAO-A and MAO-B), which are characterized by their sensitivity towards specific substrates and inhibitors. MAO-A preferentially deaminates serotonin and norepinephrine, and is selectively inhibited by clorgyline. However, MAO-B preferentially deaminates b-phenylethylamine and benzylamine, and is selectively inhibited by l-deprenyl and pargyline. 4,5) The inhibitors of MAO-A are expected to be clinically useful to treat depression and anxiety, while those of MAO-B appear to be helpful in the prevention and adjunct treatment of Parkinson's disease.6,7) A number of inhibitors of MAO activity such as quinolines, 8,9) isoquinolines, 10-12) coumarins, 13,14) and xanthones 15,16) have been reported. As a part of our ongoing research for MAO inhibitors from natural resources, we found that a MeOH extract from the fruits of Evodia rutaecarpa BENTHAM (Rutaceae) strongly inhibited the MAO activity in mouse brain. The MeOH extract was, therefore, subjected to the bioactivity-guided fractionations to isolate the active compound. The finally purified bioactive substance, compound 1 (Fig. 1), was identified by comparison of its spectral data as 1-methyl-2-undecyl-4(1H)-quinolone and was shown to be a selective inhibitor on MAO-B. Results and DiscussionIn the search for MAO inhibitors from the medicinal plants, we found that CH 2 Cl 2 fraction of the dried unripe fruits of E. rutaecarpa showed the potent inhibitory effects on MAO in mouse brain. A CH 2 Cl 2 fraction of E. rutaecarpa at a concentration of 200 mg/ml (89.1% inhibition) showed a potent inhibitory activity against MAO in mouse brain. Activity-guided separation and purification of the extract yielded a known quinolone alkaloid, 1-methyl-2-undecyl-4(1H)-quinolone (1) as an active compound (Fig. 1). The structure was identified by comparison with the physical properties and spectral data (UV, IR, MS, 1 H-and 13 C-NMR) with literature values. 17,18) Compound 1 inhibited MAO activity in a concentrationdependent manner and the IC 50 value was 35.2 mM: compound 1 exhibited a less inhibitory effect than iproniazid (IC 50 value: 12.5 mM) which was used as a positive control (data not shown).The inhibitory activity of compound 1 against MAO-A and MAO-B activities in mouse brain were investigated. lDeprenyl-treated MAO preparation was used for the measurement of MAO-A activity, and a clorgyline-treated one was for MAO-B. MAO-A activity in our preparations was about 32% of the total MAO activity and MAO-B activity was about 61% (Table 1).Compound 1 preferentially inhibited the MAO-B activity than MAO-A activity in a concentration-dependent manner with the IC 50 values of 15.3 and 338.2 mM, respectively (Table 1). These data indicate that compound 1 is a potent inhibitor for MAO-B activity.According ...

Biologically active quinoline and quinazoline alkaloids part I

“…310 1-Methyl-2-undecylquinolin-4(1 H )-one ( 165 ), an Evodia alkaloid, acted as an irreversible and selective inhibitor of type B monoamine oxidase. 311…”

Monoamine oxidase B inhibitor, selegiline, reduces 18F-THK5351 uptake in the human brain

“…Rather than PHF, the basal ganglia typically express high concentrations of aminergic projections, neuroreceptors, and their degrading enzymes such as monoamine oxidase (MAO) [4, 5]. As such, it is plausible to hypothesize that MAO-B (EC 1.4.3.4) constitutes a 18 F-THK5351 off-target binding site, particularly given its previous reported affinity to quinolone derivatives [6]. Furthermore, the presence of high concentrations of MAO-B in the human cortex demands a careful examination of the impact of MAO-B binding on 18 F-THK5351 images.…”

Development and validation of an UPLC-ESI-MS/MS method for determination of dehydroevodiamine, limonin, evodiamine, and rutaecarpine in Evodiae Fructus

“…Alkaloids are traditionally regarded as the major bioactive compounds in EF not only because a number of types of alkaloids were isolated from the herb,[121314] but also pharmacological and clinical studies indicated that alkaloids from EF had antipolysarcous,[15] cardiotonic,[1617] central stimulative,[18] vasodilatory,[1920] and anticancer activities. [212223] Evodiamine and rutaecarpine were specified as the biomarkers for quality assessment on EF in Chinese Pharmacopoeia (CP) (edition 2005),[24] and another compound, limonin, was used combined with evodiamine and rutaecarpine in CP (edition 2010)[1] for better assessment on this herb.…”