Marco-Contelles José, León Rafael, de los Ríos Cristóbal, Samadi Abdelouahid, Bartolini Manuela, Andrisano Vincenza, Huertas Oscar, Barril Xavier, Luque F Javier, Rodríguez-Franco María I, López Beatriz, López Manuela G, García Antonio G, Carreiras María do Carmo, Villarroya Mercedes
Laboratorio de Radicales Libres (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
J Med Chem. 2009 May 14;52(9):2724-32. doi: 10.1021/jm801292b.
Tacripyrines (1-14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC(50) 105 +/- 15 nM) is associated to a 30.7 +/- 8.6% inhibition of the proaggregating action of AChE on the Abeta and a moderate inhibition of Abeta self-aggregation (34.9 +/- 5.4%). Molecular modeling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11. Tacripyrines are neuroprotective agents, show moderate Ca(2+) channel blocking effect, and cross the blood-brain barrier, emerging as lead candidates for treating AD.
他克林吡啶类化合物（1 - 14）是通过将乙酰胆碱酯酶抑制剂（他克林）与钙拮抗剂（如尼莫地平）结合设计而成，旨在开发一种多靶点治疗策略来对抗阿尔茨海默病（AD）。他克林吡啶类化合物在纳摩尔范围内是选择性且强效的乙酰胆碱酯酶抑制剂。化合物11对人乙酰胆碱酯酶（hAChE）活性的混合型抑制（IC(50) 105 ± 15 nM）与该酶对β淀粉样蛋白（Aβ）促聚集作用30.7 ± 8.6%的抑制以及对Aβ自身聚集的中度抑制（34.9 ± 5.4%）相关。分子模拟表明，化合物11与乙酰胆碱酯酶外周阴离子位点（PAS）的结合主要涉及（R）-11对映体，这也与对甲氧基他克林吡啶11所表现出的非竞争性抑制机制相符。他克林吡啶类化合物是神经保护剂，具有中度的钙通道阻断作用，且能穿过血脑屏障，成为治疗AD的潜在候选药物。
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