Engelbrecht Idalet, Petzer Jacobus P, Petzer Anel
Pharmaceutical Chemistry, School of Pharmacy and Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Cent Nerv Syst Agents Med Chem. 2018;18(2):115-127. doi: 10.2174/1871524918666180426125714.
The efficacy of L-dopa in the treatment of Parkinson's disease depends on its metabolic conversion to dopamine in the brain, however extensive peripheral metabolism of L-dopa diminishes its availability for uptake into the brain. L-Dopa is extensively decarboxylated in the gastrointestinal tract and peripheral tissues by Aromatic L-Amino Acid Decarboxylase (AADC), and AADC inhibitors are thus frequently combined with L-dopa therapy. When AADC is inhibited, 3-Omethylation Catalysed by Catechol-O-Methyltransferase (COMT) becomes a dominant metabolic pathway for L-dopa, and COMT inhibitors may thus also be used as adjuncts to L-dopa in Parkinson's disease. Monoamine Oxidase (MAO), in turn, metabolises dopamine in the brain, and MAO-B inhibitors may exert a dopamine sparing effect in the brain.
MATERIALS & METHODS: Based on the roles of COMT and MAO in the metabolism of L-dopa and dopamine, the present study attempts to discover novel dual inhibitors of these enzymes. For this purpose, nitrocatechol derivatives of chalcone were synthesised and evaluated as inhibitors of COMT and MAO. The chalcone class of compounds is well known to potently inhibit MAO-B, while nitrocatechol derivatives (e.g. tolcapone and entacapone) are clinically used COMT inhibitors.
The results document that all of the derivatives are high potency in vitro inhibitors of rat liver COMT with IC50 values ranging from 0.07 to 0.29 μM. Under these experimental conditions, tolcapone and entacapone display IC50 values of 0.26 µM and 0.25 µM, respectively. The chalcones are less potent as inhibitors of MAO with the most potent inhibitor possessing a Ki of 4.6 µM for the in vitro inhibition of human MAO-B.
This study shows that nitrocatechol derivatives of chalcone may act as COMT and MAO-B inhibitors, and proposes a general strategy for further enhancing MAO-B inhibition while retaining the potent COMT inhibition activity of this class.
左旋多巴治疗帕金森病的疗效取决于其在脑内代谢转化为多巴胺，然而左旋多巴在周围组织的广泛代谢减少了其进入脑内的可用性。左旋多巴在胃肠道和周围组织中被芳香族L-氨基酸脱羧酶（AADC）广泛脱羧，因此AADC抑制剂常与左旋多巴联合使用。当AADC被抑制时，儿茶酚-O-甲基转移酶（COMT）催化的3-O-甲基化成为左旋多巴的主要代谢途径，因此COMT抑制剂也可作为帕金森病左旋多巴治疗的辅助药物。单胺氧化酶（MAO）则在脑内代谢多巴胺，MAO-B抑制剂可能在脑内发挥节省多巴胺的作用。
基于COMT和MAO在左旋多巴和多巴胺代谢中的作用，本研究试图发现这些酶的新型双重抑制剂。为此，合成了查尔酮的硝基邻苯二酚衍生物，并评估其作为COMT和MAO抑制剂的活性。已知查尔酮类化合物能有效抑制MAO-B，而硝基邻苯二酚衍生物（如托卡朋和恩他卡朋）是临床使用的COMT抑制剂。
结果表明，所有衍生物都是大鼠肝脏COMT的高效体外抑制剂，IC50值在0.07至0.29μM之间。在这些实验条件下，托卡朋和恩他卡朋的IC50值分别为0.26μM和0.25μM。查尔酮作为MAO抑制剂的活性较低，最有效的抑制剂对人MAO-B体外抑制的Ki值为4.6μM。
本研究表明，查尔酮的硝基邻苯二酚衍生物可能作为COMT和MAO-B抑制剂，并提出了一种在保留该类化合物强效COMT抑制活性的同时进一步增强MAO-B抑制作用的通用策略。
