Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Bioorg Med Chem. 2010 Feb;18(3):1018-28. doi: 10.1016/j.bmc.2009.12.064. Epub 2010 Jan 6.
Based on recent reports that several (E)-8-styrylcaffeinyl analogues are potent reversible inhibitors of monoamine oxidase B (MAO-B), a series of 8-benzyloxycaffeinyl analogues were synthesized and evaluated as inhibitors of baboon liver MAO-B and recombinant human MAO-A and -B. The 8-benzyloxycaffeinyl analogues were found to inhibit reversibly both MAO isoforms with enzyme-inhibitor dissociation constants (K(i) values) ranging from 0.14 to 1.30 microM for the inhibition of human MAO-A, and 0.023-0.59 microM for the inhibition of human MAO-B. The most potent MAO-A inhibitor was 8-(3-methylbenzyloxy)caffeine while 8-(3-bromobenzyloxy)caffeine was the most potent MAO-B inhibitor. The analogues inhibited human and baboon MAO-B with similar potencies. A quantitative structure-activity relationship (QSAR) study indicated that the MAO-B inhibition potencies of the 8-benzyloxycaffeinyl analogues are dependent on the Hansch lipophilicity (pi) and Hammett electronic (sigma) constants of the substituents at C-3 of the benzyloxy ring. Electron-withdrawing substituents with a high degree of lipophilicity enhance inhibition potency. These results are discussed with reference to possible binding orientations of the inhibitors within the active site cavities of MAO-A and -B.
基于最近有报道称，几种（E）-8-苯乙烯基咖啡因类似物是单胺氧化酶 B（MAO-B）的有效可逆抑制剂，我们合成了一系列 8-苄氧基咖啡因类似物，并将其作为狒狒肝 MAO-B 和重组人 MAO-A 和 -B 的抑制剂进行了评估。研究发现，8-苄氧基咖啡因类似物可同时抑制两种 MAO 同工酶，对人 MAO-A 的抑制酶-抑制剂解离常数（K(i)值）范围为 0.14-1.30 μM，对人 MAO-B 的抑制 K(i)值范围为 0.023-0.59 μM。对 MAO-A 抑制作用最强的是 8-(3-甲基苄氧基)咖啡因，而对 MAO-B 抑制作用最强的是 8-(3-溴苄氧基)咖啡因。这些类似物对人和狒狒 MAO-B 的抑制作用具有相似的效力。定量构效关系（QSAR）研究表明，8-苄氧基咖啡因类似物对 MAO-B 的抑制作用取决于苯氧基环上 C-3 取代基的 Hansch 脂溶性（pi）和 Hammett 电子（sigma）常数。具有高疏水性的吸电子取代基可增强抑制作用。这些结果与抑制剂在 MAO-A 和 -B 活性位点空腔中的可能结合取向进行了讨论。
