Sazetidine-a, a novel ligand that desensitizes α4β2 nicotinic acetylcholine receptors without activating them
Sazetidine-a, a novel ligand that desensitizes α4β2 nicotinic acetylcholine receptors without activating them
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DOI：
10.1124/mol.106.027318
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发表时间：
2006-10-01
影响因子：
3.6
通讯作者：
Kellar, Kenneth J.
中科院分区：
文献类型：
--
作者：
Xiao, Yingxian;Fan, Hong;Kellar, Kenneth J.
神经元烟碱乙酰胆碱受体 (nAChR) 是遍布中枢和周围神经系统的配体门控离子通道。它们对于正常生理机能至关重要，并且明显与尼古丁成瘾有关。此外，它们是多种病理状况的可能治疗靶点，包括认知障碍、帕金森病和神经性疼痛。烟碱配体通常分为激动剂（或部分激动剂）、竞争性拮抗剂或非竞争性拮抗剂。 Sazetidine-A 是一种新的烟碱配体，其药理学特征与任何这些已知配体类别均不同。 Sazetidine-A 对 α 4 β 2 nAChR 亚型具有非常高的结合亲和力（K-i 约为 0.5 nM）和选择性（K-i 比率 α 3 β 4/α 4 β 2 类似于 24,000）。尽管具有高亲和力，但与尼古丁同时使用时，sazetidine-A 既不会激活 nAChR 通道功能，也不会阻止通道激活。然而，当它与受体预孵育 10 分钟时，它会有效阻断尼古丁刺激的 α 4 β 2 nAChR 功能（IC50 约为 30 nM）。 sazetidine-A 的作用可以通过其对 α 4 β 2 nAChR 静息构象的极低亲和力和其对受体脱敏状态的极高亲和力来解释。我们认为 sazetidine-A 是 nAChR 的“沉默脱敏剂”，这意味着它可以在不首先激活受体的情况下使受体脱敏。此外，比较 sazetidine-A 和尼古丁对 α 4 β 2 nAChR 的作用表明，尼古丁和其他烟碱激动剂的主要作用与受体脱敏有关，并且 sazetidine-A 有效模拟了这些作用。
Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels found throughout the central and peripheral nervous systems. They are crucial to normal physiology and have been clearly implicated in nicotine addiction. In addition, they are possible therapeutic targets in a wide range of pathological conditions, including cognitive disorders, Parkinson's disease, and neuropathic pain. Nicotinic ligands are usually classified as agonists (or partial agonists), competitive antagonists, or noncompetitive antagonists. Sazetidine-A is a new nicotinic ligand that shows a different pharmacological profile from any of these known classes of ligands. Sazetidine-A competes with very high binding affinity (K-i approximate to 0.5 nM) and selectivity for the alpha 4 beta 2 nAChR subtype (K-i ratio alpha 3 beta 4/alpha 4 beta 2 similar to 24,000). Despite its high affinity, sazetidine-A neither activates nAChR channel function nor prevents channel activation when it is applied simultaneously with nicotine. However, when it is preincubated for 10 min with the receptors, it potently blocks nicotine-stimulated alpha 4 beta 2 nAChR function (IC50 approximate to 30 nM). The action of sazetidine-A may be explained by its very low affinity for the resting conformation of the alpha 4 beta 2 nAChRs, and its very high affinity for the desensitized state of the receptor. We propose that sazetidine-A is a "silent desensitizer" of nAChRs, meaning that it desensitizes the receptor without first activating it. Furthermore, comparison of the effects of sazetidine-A and nicotine at alpha 4 beta 2 nAChRs suggests that the predominant effects of nicotine and other nicotinic agonists are related to desensitization of the receptors and that sazetidine-A potently mimics these effects.