Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa.
Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa; Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom 2520, South Africa.
Bioorg Med Chem Lett. 2022 Jul 1;67:128746. doi: 10.1016/j.bmcl.2022.128746. Epub 2022 Apr 18.
Monoamine oxidase B (MAO-B) inhibitors are established therapy for Parkinson's disease and act, in part, by blocking the MAO-catalysed metabolism of dopamine in the brain. Two propargylamine-containing MAO-B inhibitors, selegiline [(R)-deprenyl] and rasagiline, are currently used in the clinic for this purpose. These compounds are mechanism-based inactivators and, after oxidative activation, form covalent adducts with the FAD co-factor. An important consideration is that selegiline and rasagiline display specificity for MAO-B over the MAO-A isoform thus reducing the risk of tyramine-induced changes in blood-pressure. In the interest of discovering new propargylamine MAO inhibitors, the present study synthesises racemic N-propargylamine-2-aminotetralin (2-PAT), a compound that may be considered as both a six-membered ring analogue of rasagiline and a semi-rigid N-desmethyl ring-closed analogue of selegiline. The in vitro human MAO inhibition properties of this compound were measured and the results showed that 2-PAT is a 20-fold more potent inhibitor of MAO-A (IC = 0.721 µM) compared to MAO-B (IC = 14.6 µM). Interestingly, dialysis studies found that 2-PAT is a reversible MAO-A inhibitor, while acting as an inactivator of MAO-B. Since reversible MAO-A inhibitors are much less liable to potentiate tyramine-induced side effects than MAO-A inactivators, it is reasonable to suggest that 2-PAT could be a useful and safe therapeutic agent for disorders such as Parkinson's disease and depression.
单胺氧化酶 B（MAO-B）抑制剂是治疗帕金森病的有效药物，其作用机制部分是通过抑制 MAO 催化的大脑中多巴胺的代谢。两种含丙炔胺的 MAO-B 抑制剂，司来吉兰（（R）-去甲丙炔苯丙胺）和雷沙吉兰，目前临床上用于治疗该疾病。这些化合物是基于机制的失活剂，在氧化激活后，与 FAD 辅因子形成共价加合物。一个重要的考虑因素是，司来吉兰和雷沙吉兰对 MAO-B 具有特异性，而不是 MAO-A 同工酶，从而降低了酪胺引起的血压变化的风险。为了发现新的丙炔胺 MAO 抑制剂，本研究合成了外消旋 N-丙炔胺-2-氨基四氢萘（2-PAT），该化合物可以被认为是雷沙吉兰的六元环类似物和司来吉兰的半刚性 N-去甲基环封闭类似物。该化合物对人 MAO 的体外抑制特性进行了测量，结果表明，与 MAO-B（IC = 14.6 μM）相比，2-PAT 对 MAO-A 的抑制作用要强 20 倍（IC = 0.721 μM）。有趣的是，透析研究发现，2-PAT 是一种可逆的 MAO-A 抑制剂，同时也是 MAO-B 的失活剂。由于可逆的 MAO-A 抑制剂比 MAO-A 失活剂更不容易增强酪胺引起的副作用，因此可以合理地假设 2-PAT 可能是治疗帕金森病和抑郁症等疾病的有用且安全的治疗药物。
