Structural differences determine the relative selectivity of nicotinic compounds for native α4β2*-, α6β2*-, α3β4*- and α7-nicotine acetylcholine receptors
Structural differences determine the relative selectivity of nicotinic compounds for native α4β2*-, α6β2*-, α3β4*- and α7-nicotine acetylcholine receptors
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DOI：
10.1016/j.neuropharm.2010.01.013
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发表时间：
2010-06-01
影响因子：
4.7
通讯作者：
Marks, Michael J.
中科院分区：
文献类型：
--
作者：
Grady, Sharon R.;Drenan, Ryan M.;Marks, Michael J.
哺乳动物脑表达多种烟碱乙酰胆碱受体（nAChR）亚型，这些亚型在亚基组成、表达位点以及药理学和功能特性方面不同。在已知的受体亚型中，α 4 β 2* 和α 6 β 2*-nAChR对尼古丁具有最高的亲和力（其中 * 表示其他亚基的可能性）。α 4 β 2*-nAChR广泛分布，而α 6 β 2*-nAChR仅限于少数区域。这两种亚型都调节多巴胺能神经元释放多巴胺的mesoadrenbens途径被认为是必不可少的奖励和成瘾。α 4 β 2 ~*-nAChR也调节这些区域GABA的释放，选择性化合物的鉴定将有助于nAChR亚型的研究。对nAChR亚型作用的进一步了解可能有助于开发更有效的戒烟辅助手段，其副作用比目前的治疗方法更少。我们已经筛选了一系列烟碱化合物，这些化合物在吡啶和阳离子中心之间的距离、空间体积和分子的灵活性方面有所不同。使用膜结合和突触体功能测定或来自表达h α 7的GH4 C1细胞的记录来筛选这些化合物，以确定对脑中发现的四种nAChR亚型α 4 β 2*、α 6 β 2*、α 7和α 3 β 4* 的亲和力、效力和功效。此外，使用功能获得性突变小鼠中的生理测定来评估α 4 β 2* 和α 6 β 2*-nAChR的体内活性。这种方法已经鉴定出几种具有激动剂或部分激动剂活性的化合物，其显示出对α 6 β 2*-nAChR的改善的选择性。(C)2010爱思唯尔有限公司版权所有。
Mammalian brain expresses multiple nicotinic acetylcholine receptor (nAChR) subtypes that differ in subunit composition, sites of expression and pharmacological and functional properties. Among known subtypes of receptors, alpha 4 beta 2* and alpha 6 beta 2*-nAChR have the highest affinity for nicotine (where * indicates possibility of other subunits). The alpha 4 beta 2*-nAChRs are widely distributed, while alpha 6 beta 2*-nAChR are restricted to a few regions. Both subtypes modulate release of dopamine from the dopaminergic neurons of the mesoaccumbens pathway thought to be essential for reward and addiction. alpha 4 beta 2*-nAChR also modulate GABA release in these areas.Identification of selective compounds would facilitate study of nAChR subtypes. An improved understanding of the role of nAChR subtypes may help in developing more effective smoking cessation aids with fewer side effects than current therapeutics. We have screened a series of nicotinic compounds that vary in the distance between the pyridine and the cationic center, in steric bulk, and in flexibility of the molecule. These compounds were screened using membrane binding and synaptosomal function assays, or recordings from GH4C1 cells expressing h alpha 7, to determine affinity, potency and efficacy at four subtypes of nAChRs found in brain, alpha 4 beta 2*, alpha 6 beta 2*, alpha 7 and alpha 3 beta 4*. In addition, physiological assays in gain-of-function mutant mice were used to assess in vivo activity at a4 beta 2* and alpha 6 beta 2*-nAChRs. This approach has identified several compounds with agonist or partial agonist activity that display improved selectivity for alpha 6 beta 2*-nAChR. (C) 2010 Elsevier Ltd. All rights reserved.