Gerlach M, Riederer P, Youdim M B
Department of Psychiatry, University of Würzburg, Germany.
Eur J Pharmacol. 1992 Jun 5;226(2):97-108. doi: 10.1016/0922-4106(92)90170-z.
L-Deprenyl, the selective inhibitor of monoamine oxidase type B (MAO-B), has gained wide acceptance as a useful form of adjunct therapeutic drug in the treatment of Parkinson's disease. This review summarizes the molecular pharmacology of L-deprenyl, and the advances in our understanding of its possible mode of action in Parkinson's disease. L-Deprenyl belongs to the class of enzyme-activated irreversible inhibitors also described as 'suicide' inhibitors, because the compound acts as a substrate for the target enzyme, whose action on the compound results in irreversible inhibition. L-Deprenyl first of all forms a noncovalent complex with MAO as an initial, reversible step. The subsequent interaction of L-deprenyl with MAO leads to a reduction of the enzyme-bound flavin-adenine dinucleotide (FAD), and concomitant oxidation of the inhibitor. This oxidized inhibitor then reacts with FAD at the N-5-position in a covalent manner. The observed in vitro selectivity of L-deprenyl for MAO-B may be accounted for by differences in the affinities of the two MAO subtypes for reversible interaction with L-deprenyl, differences in the rates of reaction within the noncovalent complexes to form the irreversibly inhibited adduct, or a combination of both these factors. However, if selective inhibition is to be maintained in vivo, correct dosage schedules are critically important, since all selective MAO inhibitors described up to now lack selectivity at high doses. In experimental animals L-deprenyl is protective against the damaging effects of several neurotoxins, including the dopaminergic agents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) and the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). Beside MAO-B inhibition, which above all explains the prevention of neurotoxic action of MPTP by preventing its metabolism, L-deprenyl appears to exhibit other mechanisms of action which are independent of its action on MAO-B.
L-司来吉兰，单胺氧化酶B型（MAO-B）的选择性抑制剂，作为帕金森病治疗中的一种辅助治疗药物已获得广泛认可。本综述总结了L-司来吉兰的分子药理学，以及我们对其在帕金森病中可能作用方式理解的进展。L-司来吉兰属于酶激活不可逆抑制剂类别，也被称为“自杀”抑制剂，因为该化合物作为靶酶的底物，酶对化合物的作用导致不可逆抑制。L-司来吉兰首先与MAO形成非共价复合物，这是一个初始的可逆步骤。随后L-司来吉兰与MAO的相互作用导致酶结合的黄素腺嘌呤二核苷酸（FAD）还原，同时抑制剂被氧化。然后这种氧化的抑制剂与FAD在N-5位以共价方式反应。观察到的L-司来吉兰对MAO-B的体外选择性可能是由于两种MAO亚型与L-司来吉兰可逆相互作用的亲和力差异、非共价复合物内形成不可逆抑制加合物的反应速率差异，或这两种因素的组合。然而，如果要在体内维持选择性抑制，正确的给药方案至关重要，因为到目前为止描述的所有选择性MAO抑制剂在高剂量时都缺乏选择性。在实验动物中，L-司来吉兰对几种神经毒素的损伤作用具有保护作用，包括多巴胺能剂1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）和6-羟基多巴胺（6-OHDA）以及去甲肾上腺素能神经毒素N-（2-氯乙基）-N-乙基-2-溴苄胺（DSP-4）。除了抑制MAO-B（这首先解释了通过阻止MPTP代谢来预防其神经毒性作用）之外，L-司来吉兰似乎还表现出其他独立于其对MAO-B作用的作用机制。
