Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, USA.
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, USA.
Nitric Oxide. 2019 Jan 1;82:59-74. doi: 10.1016/j.niox.2018.10.006. Epub 2018 Oct 28.
The development of small molecule modulators of NO/cGMP signaling for use in the CNS has lagged far behind the use of such clinical agents in the periphery, despite the central role played by NO/cGMP in learning and memory, and the substantial evidence that this signaling pathway is perturbed in neurodegenerative disorders, including Alzheimer's disease. The NO-chimeras, NMZ and Nitrosynapsin, have yielded beneficial and disease-modifying responses in multiple preclinical animal models, acting on GABA and NMDA receptors, respectively, providing additional mechanisms of action relevant to synaptic and neuronal dysfunction. Several inhibitors of cGMP-specific phosphodiesterases (PDE) have replicated some of the actions of these NO-chimeras in the CNS. There is no evidence that nitrate tolerance is a phenomenon relevant to the CNS actions of NO-chimeras, and studies on nitroglycerin in the periphery continue to challenge the dogma of nitrate tolerance mechanisms. Hybrid nitrates have shown much promise in the periphery and CNS, but to date only one treatment has received FDA approval, for glaucoma. The potential for allosteric modulation of soluble guanylate cyclase (sGC) in brain disorders has not yet been fully explored nor exploited; whereas multiple applications of PDE inhibitors have been explored and many have stalled in clinical trials.
小分子一氧化氮/环鸟苷酸信号转导调节剂在中枢神经系统中的应用发展远远落后于其在外周神经系统中的应用，尽管一氧化氮/环鸟苷酸在学习和记忆中发挥着核心作用，而且有大量证据表明这种信号通路在神经退行性疾病中受到干扰，包括阿尔茨海默病。NO 嵌合体 NMZ 和 Nitrosynapsin 分别作用于 GABA 和 NMDA 受体，在多种临床前动物模型中产生了有益的和疾病改善的反应，为突触和神经元功能障碍提供了额外的作用机制。几种环鸟苷酸特异性磷酸二酯酶 (PDE) 的抑制剂在中枢神经系统中复制了这些 NO 嵌合体的一些作用。目前没有证据表明硝酸盐耐受是与 NO 嵌合体在中枢神经系统中的作用相关的现象，并且有关外周血硝酸盐的研究继续挑战硝酸盐耐受机制的教条。杂种硝酸盐在外周和中枢神经系统中都显示出很大的希望，但迄今为止，只有一种治疗方法获得了 FDA 的批准，用于治疗青光眼。尚未充分探索和利用大脑疾病中可溶性鸟苷酸环化酶 (sGC) 的变构调节潜力；而 PDE 抑制剂的多种应用已经被探索，许多在临床试验中停滞不前。
