O'Brien E M, Tipton K F, Meroni M, Dostert P
Department of Biochemistry, Trinity College, Dublin, Ireland.
J Neural Transm Suppl. 1994;41:295-305. doi: 10.1007/978-3-7091-9324-2_39.
N-Methyl-N-propargyl-3-(4-phenoxy)phenoxypropylamine, an analogue of the MAO-A-selective irreversible inhibitor clorgyline in which the 2,4-dichloro- substitution in clorgyline was replaced by a 2-H atom and a 4-phenoxy group, has been synthesised and assessed as an inhibitor of monoamine oxidase (MAO). This compound proved to be a time-dependent irreversible inhibitor of both MAO-A and -B. However, unlike clorgyline, it was selective towards MAO-B, both in its initial, non-covalent, binding to the enzyme and as an irreversible inhibitor. In order to assess the influence of side-chain length on inhibitory potency, analogues were synthesised in which the side-chain was reduced to 2 CH2 units (N-methyl-N-propargyl-2- (4-phenoxy)phenoxyethylamine) or increased to 4 CH2 units (N-methyl-N-propargyl-4-(4- phenoxy)phenoxybutylamine). Both these compounds were also time-dependent irreversible inhibitors with selectivity towards MAO-B. In the case of the initial, non-covalent, inhibition all these compounds were competitive inhibitors of MAO-A, with respect to the amine substrate, and the affinity for inhibitor binding increased with carbon chain length. In contrast the compounds were all mixed inhibitors of MAO-B. The competitive element of this inhibition (measured by Kis) was similar for the 2 and 3 carbon-chain compounds but decreased markedly when the chain-length was increased to 4 carbons. The uncompetitive inhibition (measured by Kii) decreased as the carbon chain-length was increased from 2 to 3, but there was no significant further change when the length was increased to 4 carbons. The time-dependent irreversible inhibition (measured as the IC50 values after 60 min enzyme-inhibitor preincubation) showed that the potency towards MAO-A increased when the side-chain length was increased from 2 to 3 carbons but that there was no significant difference between the 3 and 4 carbon-chain compounds. In the case of MAO-B inhibition, the 2 and 3 carbon-chain compounds had similar inhibitory potencies but this increased substantially when the chain length was increased to 4 carbons. The significance of the inhibitory behaviour of these compounds is discussed in terms of the structure-activity relationships of mechanism-based irreversible MAO inhibitors.
N-甲基-N-炔丙基-3-(4-苯氧基)苯氧基丙胺是单胺氧化酶-A（MAO-A）选择性不可逆抑制剂氯吉兰的类似物，其中氯吉兰的2,4-二氯取代基被一个2-H原子和一个4-苯氧基取代。该化合物已被合成并作为单胺氧化酶（MAO）的抑制剂进行评估。结果证明，该化合物是MAO-A和MAO-B的时间依赖性不可逆抑制剂。然而，与氯吉兰不同的是，它在与酶的初始非共价结合以及作为不可逆抑制剂时，对MAO-B具有选择性。为了评估侧链长度对抑制效力的影响，合成了侧链减少为2个CH2单元的类似物（N-甲基-N-炔丙基-2-(4-苯氧基)苯氧基乙胺）或增加到4个CH2单元的类似物（N-甲基-N-炔丙基-4-(4-苯氧基)苯氧基丁胺）。这两种化合物也是时间依赖性不可逆抑制剂，对MAO-B具有选择性。在初始非共价抑制的情况下，所有这些化合物都是MAO-A相对于胺底物的竞争性抑制剂，并且抑制剂结合的亲和力随着碳链长度的增加而增加。相反，这些化合物都是MAO-B的混合型抑制剂。这种抑制的竞争性成分（通过Kis测量）对于2碳链和3碳链化合物相似，但当链长增加到4个碳时显著降低。非竞争性抑制（通过Kii测量）随着碳链长度从2增加到3而降低，但当长度增加到4个碳时没有进一步的显著变化。时间依赖性不可逆抑制（在酶-抑制剂预孵育60分钟后测量IC50值）表明，当侧链长度从2个碳增加到3个碳时，对MAO-A的效力增加，但3碳链和4碳链化合物之间没有显著差异。在MAO-B抑制方面，2碳链和3碳链化合物具有相似的抑制效力，但当链长增加到4个碳时，抑制效力大幅增加。根据基于机制的不可逆MAO抑制剂的构效关系，讨论了这些化合物抑制行为的意义。
