Pharmaceutical Chemistry, School of Pharmacy, Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Pharmaceutical Chemistry, School of Pharmacy, Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Eur J Med Chem. 2017 Jul 28;135:196-203. doi: 10.1016/j.ejmech.2017.04.055. Epub 2017 Apr 22.
The monoamine oxidase (MAO) enzymes are of considerable pharmacological interest and inhibitors are used in the clinic for the treatment of major depressive disorder and Parkinson's disease. A limited number of studies have shown that the quinone class of compounds possesses MAO inhibition properties. Most notable among these is a report that 2,3,6-trimethyl-1,4-naphthoquinone (TMN), present in extracts of cured tobacco leafs, is a non-selective inhibitor of both MAO isoforms. An older study reports that 1,4-benzoquinone inhibits MAO-A and MAO-B from human synaptosomes. Both 1,4-naphthoquinones and 1,4-benzoquinone are reported to inhibit the MAOs with a reversible mode of action. Since the MAO inhibition properties of additional members of the 1,4-benzoquinone class of compounds have not yet been explored, the present study investigates a small series of four 1,4-benzoquinones which incorporate phenyl, benzyl, benzyloxy and cyclopentyl monosubstitution on C2. The 1,4-benzoquinones were found to be moderately potent MAO inhibitors with IC values of 5.03-13.2 μM (MAO-A) and 3.69-23.2 μM (MAO-B). These values are comparable to those recorded for 1,4-benzoquinone of 4.82 μM (MAO-A) and 10.2 μM (MAO-B). Of interest however, is the finding that the 1,4-benzoquinones are irreversible inhibitors of MAO-A since prolonged incubation results in near complete inhibition, and enzyme activity is not recovered by dialysis. MAO-B is much less sensitive to inactivation by the 1,4-benzoquinones. These findings are discussed with reference to a possible mechanism by which irreversible inhibition occurs. It may be concluded that irreversible 1,4-benzoquinone-derived inhibitors may act as probes for investigating quinone reactive sites in the MAOs.
单胺氧化酶（MAO）酶具有重要的药理学意义，抑制剂被用于临床治疗重度抑郁症和帕金森病。少数研究表明，醌类化合物具有 MAO 抑制作用。其中最值得注意的是一项报告称，存在于熏制烟叶提取物中的 2,3,6-三甲基-1,4-萘醌（TMN）是两种 MAO 同工酶的非选择性抑制剂。一项较早的研究报告称，1,4-苯醌抑制人突触体中的 MAO-A 和 MAO-B。1,4-萘醌和 1,4-苯醌都被报道以可逆的作用方式抑制 MAO。由于尚未探索 1,4-苯醌类化合物的其他成员的 MAO 抑制特性，本研究调查了一小系列四种在 C2 上引入苯基、苄基、苯氧基和环戊基单取代的 1,4-苯醌。发现 1,4-苯醌是中度有效的 MAO 抑制剂，IC 值为 5.03-13.2 μM（MAO-A）和 3.69-23.2 μM（MAO-B）。这些值与 1,4-苯醌的 4.82 μM（MAO-A）和 10.2 μM（MAO-B）的记录值相当。然而，有趣的是，发现 1,4-苯醌是 MAO-A 的不可逆抑制剂，因为长时间孵育会导致几乎完全抑制，并且酶活性不能通过透析恢复。MAO-B 对 1,4-苯醌的失活不那么敏感。这些发现与不可逆抑制发生的可能机制有关。可以得出结论，不可逆的 1,4-苯醌衍生抑制剂可能作为研究 MAO 中醌反应性位点的探针。
