BACKGROUND AND PURPOSE The α3β4 subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediating nicotine reinforcement processes. AT-1001 has been recently described as a high-affinity and selective α3β4 nAChR antagonist that blocks nicotine self-administration in rats. The aim of this study was to investigate the mechanism of action underlying the nicotine-suppressive effects of AT-1001. EXPERIMENTAL APPROACH Effects of AT-1001 were determined using in vitro assays and rat models of nicotine addiction, and compared with varenicline. KEY RESULTS AT-1001 and its analogue AT-1012 were functionally selective as antagonists for α3β4 over α4β2 nAChRs, but not to the same extent as the binding selectivity, and had partial agonist activity at α3β4 nAChRs. In contrast, varenicline was a partial agonist at α4β2, a weak agonist at α3β4 and inhibited α4β2 at a much lower concentration than it inhibited α3β4 nAChRs. AT-1001 and varenicline also had very different in vivo properties. Firstly, AT-1001 did not exhibit reinforcing properties per se while varenicline was self-administered. Secondly, systemic treatment with AT-1001 did not induce reinstatement of nicotine seeking but rather attenuated reinstatement induced by varenicline, as well as nicotine. Finally, unlike varenicline, AT-1001 selectively blocked nicotine self-administration without altering alcohol lever pressing as assessed in an operant co-administration paradigm. CONCLUSIONS AND IMPLICATIONS These findings describe a more complex AT-1001 in vitro profile than previously appreciated and provide further support for the potential of AT-1001 and congeners as clinically useful compounds for smoking cessation, with a mechanism of action distinct from currently available medications.

中文翻译：

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AT-1001：具有新型尼古丁抑制药理学的高亲和力 α3β4 nAChR 配体。

背景和目的 烟碱乙酰胆碱受体 (nAChR) 的 α3β4 亚型与介导烟碱强化过程有关。AT-1001 最近被描述为一种高亲和力和选择性的 α3β4 nAChR 拮抗剂，可阻断大鼠的尼古丁自我给药。本研究的目的是研究 AT-1001 尼古丁抑制作用的潜在作用机制。实验方法使用体外试验和尼古丁成瘾大鼠模型确定 AT-1001 的作用，并与伐尼克兰进行比较。主要结果 AT-1001 及其类似物 AT-1012 作为 α3β4 拮抗剂的功能选择性高于 α4β2 nAChR，但与结合选择性的程度不同，并且对 α3β4 nAChR 具有部分激动剂活性。相比之下，伐尼克兰是 α4β2 的部分激动剂，α3β4 的弱激动剂，并且在比抑制 α3β4 nAChR 低得多的浓度下抑制 α4β2。AT-1001 和伐尼克兰也具有非常不同的体内特性。首先，AT-1001 本身没有表现出增强特性，而伐尼克兰是自我给药的。其次，用 AT-1001 全身治疗不会诱导尼古丁寻求的恢复，而是减弱了由伐尼克兰和尼古丁诱导的恢复。最后，与伐尼克兰不同，AT-1001 选择性地阻止尼古丁自我给药，而不改变酒精杠杆压力，如在操作性共同给药范例中评估的那样。