Xiao Yingxian, Fan Hong, Musachio John L, Wei Zhi-Liang, Chellappan Sheela K, Kozikowski Alan P, Kellar Kenneth J
Department of Pharmacology, Georgetown University School of Medicine, Washington, DC 20057, USA.
Mol Pharmacol. 2006 Oct;70(4):1454-60. doi: 10.1124/mol.106.027318. Epub 2006 Jul 20.
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 (Ki approximately 0.5 nM) and selectivity for the alpha4beta2 nAChR subtype (Ki ratio alpha3beta4/alpha4beta2 approximately 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 pre-incubated for 10 min with the receptors, it potently blocks nicotine-stimulated alpha4beta2 nAChR function (IC50 approximately 30 nM). The action of sazetidine-A may be explained by its very low affinity for the resting conformation of the alpha4beta2 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 alpha4beta2 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.
神经元烟碱型乙酰胆碱受体（nAChRs）是遍布中枢和外周神经系统的配体门控离子通道。它们对正常生理功能至关重要，并且在尼古丁成瘾中有着明确的关联。此外，它们在包括认知障碍、帕金森病和神经性疼痛等多种病理状况下可能成为治疗靶点。烟碱型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。沙泽替丁 - A是一种新型烟碱型配体，其药理学特征与这些已知类型的配体均不同。沙泽替丁 - A以非常高的结合亲和力（Ki约为0.5 nM）与α4β2 nAChR亚型竞争，且具有选择性（α3β4/α4β2的Ki比值约为24,000）。尽管具有高亲和力，但沙泽替丁 - A既不激活nAChR通道功能，在与尼古丁同时应用时也不阻止通道激活。然而，当它与受体预孵育10分钟时，它能有效阻断尼古丁刺激的α4β2 nAChR功能（IC50约为30 nM）。沙泽替丁 - A的作用可能是由于其对α4β2 nAChRs静息构象的亲和力非常低，而对受体脱敏状态的亲和力非常高。我们提出沙泽替丁 - A是nAChRs的“沉默脱敏剂”，即它在不首先激活受体的情况下使其脱敏。此外，沙泽替丁 - A和尼古丁对α4β2 nAChRs作用的比较表明，尼古丁和其他烟碱型激动剂的主要作用与受体脱敏有关，并且沙泽替丁 - A能有效模拟这些作用。
