Pharmacological manipulation of cGMP and NO/cGMP in CNS drug discovery.
Pharmacological manipulation of cGMP and NO/cGMP in CNS drug discovery.
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DOI：
10.1016/j.niox.2018.10.006
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发表时间：
2019-01-01
期刊：
影响因子：
--
通讯作者：
Thatcher GRJ
中科院分区：
文献类型：
--
作者：
Hollas MA;Ben Aissa M;Lee SH;Gordon-Blake JM;Thatcher GRJ
尽管NO/cGMP在学习和记忆中发挥着核心作用，但用于中枢神经系统的NO/cGMP信号小分子调节剂的开发远远落后于此类临床药物的使用，而且有大量证据表明，这一信号通路在包括阿尔茨海默病在内的神经退行性疾病中受到干扰。非嵌合体NMZ和Nitrosynapsin分别作用于GABAA和NMDA受体，在多种临床前动物模型中产生了有益的和改善疾病的反应，提供了与突触和神经元功能障碍相关的额外作用机制。几种cGMP特异性磷酸二酯酶(PDE)的抑制剂已经在中枢神经系统复制了这些非嵌合体的一些作用。没有证据表明硝酸盐耐受是一种与非嵌合体的中枢神经系统活动相关的现象，外围对硝酸甘油的研究继续挑战硝酸盐耐受机制的教条。混合硝酸盐在外周和中枢神经系统显示出很大的前景，但到目前为止，只有一种治疗方法获得了FDA的批准，那就是青光眼。可溶性鸟苷环化酶(SGC)在脑部疾病中的变构调节作用尚未被充分探索和开发，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。
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 GABAA 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.
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