Yu P H, Davis B A, Boulton A A
Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada.
J Med Chem. 1992 Oct 2;35(20):3705-13. doi: 10.1021/jm00098a017.
A series of aliphatic propargylamine derivatives has been synthesized. Some of them possess highly potent, irreversible, selective, inhibitory activity toward monoamine oxidase B (MAO-B). The potency of the inhibitors is related to chain length and substitution of a hydrogen on the terminal carbon of the aliphatic chain. MAO inhibitory activity as assessed in vitro increased as the aliphatic carbon chain length increased. Substitution of a hydrogen by hydroxyl, carboxyl, or carbethoxyl groups at the aliphatic chain terminal or replacement of the methyl group on the nitrogen atom by an ethyl group considerably reduced the inhibitory activity. Stereospecific effects were observed with the R-(-)-enantiomer being 20-fold more active than the S-(+)-enantiomer. Inhibitors with relatively short carbon chain lengths (i.e. four to six carbons) were found to be more potent than those with longer chains in inhibiting brain MAO-B activity in vivo especially after oral administration. Chronic administration of low doses of the aliphatic propargylamines caused a slight cumulative inhibition of MAO-A activity in the mouse brain. These MAO-B inhibitors appear to be nontoxic, and they do not possess an amphetamine-like moiety in their structure as is the case for deprenyl. We expect that these aliphatic propargylamines may be useful in the treatment in certain neuropsychiatric disorders.
已经合成了一系列脂肪族炔丙胺衍生物。其中一些对单胺氧化酶B（MAO - B）具有高效、不可逆、选择性抑制活性。抑制剂的效力与脂肪链长度以及脂肪链末端碳原子上氢的取代情况有关。体外评估的MAO抑制活性随着脂肪族碳链长度的增加而增强。在脂肪链末端用羟基、羧基或乙氧羰基取代氢，或者将氮原子上的甲基用乙基取代，会显著降低抑制活性。观察到立体特异性效应，R - (-)-对映体的活性比S - (+)-对映体高20倍。发现碳链长度相对较短（即四到六个碳）的抑制剂在体内抑制脑MAO - B活性方面比碳链较长的抑制剂更有效，尤其是在口服给药后。长期低剂量给予脂肪族炔丙胺会对小鼠脑中的MAO - A活性产生轻微的累积抑制作用。这些MAO - B抑制剂似乎无毒，并且它们的结构中不像司来吉兰那样含有类似苯丙胺的部分。我们期望这些脂肪族炔丙胺可能对某些神经精神疾病的治疗有用。
