The α4β2 nAChR is the most predominant subtype in the brain and is a well-known culprit for nicotine addiction. Previously we presented a series of α4β2 nAChR selective compounds that were discovered from a mixture-based positional-scanning combinatorial library. Here we report further optimization identified highly potent and selective α4β2 nAChR antagonists 5 (AP-202) and 13 (AP-211). Both compounds are devoid of in vitro agonist activity and are potent inhibitors of epibatidine-induced changes in membrane potential in cells containing α4β2 nAChR, with IC₅₀ values of approximately 10 nM, but are weak agonists in cells containing α3β4 nAChR. In vivo studies show that 5 can significantly reduce operant nicotine self-administration and nicotine relapse-like behavior in rats at doses of 0.3 and 1 mg/kg. The pharmacokinetic data also indicate that 5, via sc administration, is rapidly absorbed into the blood, reaching maximal concentration within 10 min with a half-life of less than 1 h.

中文翻译：

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选择性强的α4β2nAChR拮抗药抑制大鼠尼古丁的自我管理和恢复

α4β2nAChR是大脑中最主要的亚型，并且是尼古丁成瘾的众所周知的罪魁祸首。以前，我们介绍了从基于混合物的位置扫描组合库中发现的一系列α4β2nAChR选择性化合物。在这里，我们报告了进一步的优化，确定了高效且选择性强的α4β2nAChR拮抗剂5（AP-202）和13（AP-211）。两种化合物都没有体外激动剂活性，并且是含有α4β2nAChR的细胞中依巴替丁诱导的膜电位变化的有效抑制剂，IC ₅₀值约为10 nM，但在含有α3β4nAChR的细胞中是弱的激动剂。体内研究表明5可以在0.3和1 mg / kg的剂量下显着降低大鼠的操作性尼古丁自我给药和类似尼古丁复发的行为。药代动力学数据还表明5通过皮下注射迅速吸收到血液中，在10分钟内达到最大浓度，半衰期少​​于1小时。