Nicotinic receptor antagonists as treatments for nicotine abuse.
Nicotinic receptor antagonists as treatments for nicotine abuse.
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DOI：
10.1016/b978-0-12-420118-7.00013-5
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Dwoskin, Linda P
中科院分区：
文献类型：
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作者：
Crooks, Peter A;Bardo, Michael T;Dwoskin, Linda P
尽管目前的药物疗法对烟草依赖的疗效已得到证实，但复发率仍然很高，这表明需要新的药物。目前，有几种戒烟剂可供使用，包括伐尼克兰（Chantix®）、安非他酮（Zyban®）和金雀花碱（Tabex®）。伐尼克兰和金雀花碱是α4β2* 烟碱乙酰胆碱受体（nAChR）的部分激动剂。安非他酮是一种抗抑郁药，但也是α3β2* 神经节nAChR的拮抗剂。尼古丁的奖赏效应部分由尼古丁诱发的多巴胺（DA）释放介导，导致致敏，这与重复尼古丁给药和尼古丁成瘾有关。选择性靶向介导尼古丁诱发的DA释放的中枢nAChR亚型的受体拮抗剂应具有作为烟草使用停止剂的功效，具有有限副作用特征的治疗优势。而α-芋螺毒素MII（α-CtxMII）不敏感的nAChR（例如，α4β2*）参与尼古丁诱发的DA释放，这些nAChR广泛分布于大脑中，抑制这些受体可能导致非选择性和不良反应。相比之下，α-CtxMII-敏感的nAChRs介导尼古丁诱发的DA释放提供了作为戒烟靶点的优势，因为它们主要局限于多巴胺能神经元。现已鉴定出小药物样分子，其是α-CtxMII敏感nAChR亚型（包含α6和β2亚基）的选择性拮抗剂。早期的研究确定了多种季铵类似物，它们是nAChR介导尼古丁诱发的DA释放的有效和选择性拮抗剂。最近的数据表明，新型非季铵双-1，2，5，6-四氢吡啶类似物通过作为α-CtxMII敏感nAChR亚型的拮抗剂，在体外有效抑制（IC 50 <1 nM）尼古丁诱发的DA释放;这些化合物还减少了大鼠的NIC自我给药。
Despite the proven efficacy of current pharmacotherapies for tobacco dependence, relapse rates continue to be high, indicating that novel medications are needed. Currently, several smoking cessation agents are available, including varenicline (Chantix®), bupropion (Zyban®), and cytisine (Tabex®). Varenicline and cytisine are partial agonists at the α4β2* nicotinic acetylcholine receptor (nAChR). Bupropion is an antidepressant but is also an antagonist at α3β2* ganglionic nAChRs. The rewarding effects of nicotine are mediated, in part, by nicotine-evoked dopamine (DA) release leading to sensitization, which is associated with repeated nicotine administration and nicotine addiction. Receptor antagonists that selectivity target central nAChR subtypes mediating nicotine-evoked DA release should have efficacy as tobacco use cessation agents with the therapeutic advantage of a limited side-effect profile. While α-conotoxin MII (α-CtxMII)-insensitive nAChRs (e.g., α4β2*) contribute to nicotine-evoked DA release, these nAChRs are widely distributed in the brain, and inhibition of these receptors may lead to nonselective and untoward effects. In contrast, α-CtxMII-sensitive nAChRs mediating nicotine-evoked DA release offer an advantage as targets for smoking cessation, due to their more restricted localization primarily to dopaminergic neurons. Small drug-like molecules that are selective antagonists at α-CtxMII-sensitive nAChR subtypes that contain α6 and β2 subunits have now been identified. Early research identified a variety of quaternary ammonium analogs that were potent and selective antagonists at nAChRs mediating nicotine-evoked DA release. More recent data have shown that novel, non-quaternary bis-1,2,5,6-tetrahydropyridine analogs potently inhibit (IC50<1 nM) nicotine-evoked DA release in vitro by acting as antagonists at α-CtxMII-sensitive nAChR subtypes; these compounds also decrease NIC self-administration in rats.