Perola E, Cellai L, Lamba D, Filocamo L, Brufani M
Istituto di Strutturistica Chimica Giordano Giacomello, CNR, CP10, Rome, Italy.
Biochim Biophys Acta. 1997 Nov 14;1343(1):41-50. doi: 10.1016/s0167-4838(97)00133-7.
Heptylphysostigmine is in advanced clinical trial as a drug for Alzheimer's disease. 8-Morpholinooctylphysostigmine and 8-(cis-2,6-dimethylmorpholino)octylphysostigmine are currently undergoing pre-clinical evaluation. The mechanism of action of these compounds in the inhibition of acetylcholinesterase has been investigated. All the examined compounds display non competitive-like kinetics of inhibition. There are no reversible components in the observed inhibition: the whole inhibitory effect is due to the time-dependent pseudo-irreversible carbamylation of the active site. Yet the observed time course of the inhibition does not match a simple second order kinetics. An influence of the quaternary structure of the enzyme on the more complex kinetics of carbamylation is hypothesized. Reactivation experiments on the inhibited enzyme show long lasting inhibitory effects for these compounds. The higher duration of the anticholinesterase effect of the morpholino derivatives compared to heptylphysostigmine should provide the basis for their higher therapeutic potential.
庚基毒扁豆碱作为一种治疗阿尔茨海默病的药物正处于临床试验后期。8-吗啉代辛基毒扁豆碱和8-（顺式-2,6-二甲基吗啉代）辛基毒扁豆碱目前正在进行临床前评估。已对这些化合物抑制乙酰胆碱酯酶的作用机制进行了研究。所有检测的化合物均表现出非竞争性抑制动力学。在观察到的抑制作用中没有可逆成分：整个抑制作用是由于活性位点的时间依赖性假不可逆氨甲酰化。然而，观察到的抑制时间进程并不符合简单的二级动力学。推测酶的四级结构对更复杂的氨甲酰化动力学有影响。对被抑制酶的复活实验表明这些化合物具有持久的抑制作用。与庚基毒扁豆碱相比，吗啉代衍生物的抗胆碱酯酶作用持续时间更长，这应为其更高的治疗潜力提供依据。
