Desensitization of Nicotinic Acetylcholine Receptors as a Strategy for Drug Development
Desensitization of Nicotinic Acetylcholine Receptors as a Strategy for Drug Development
复制标题
DOI：
10.1124/jpet.108.145292
复制
发表时间：
2009-02-01
影响因子：
3.5
通讯作者：
Terry, Alvin V., Jr.
中科院分区：
文献类型：
--
作者：
Buccafusco, Jerry J.;Beach, J. Warren;Terry, Alvin V., Jr.
由烟碱乙酰胆碱受体（nAChR）激动剂诱发的特异性药理学反应由每种受体亚型的解剖学分布和表达以及由包含每种亚型的亚基的化学计量决定。促成这种复杂性的是结合受体的正构位点的激动剂改变受体的亲和力状态并诱导脱敏的能力，以及在低剂量下，一些nAChR拮抗剂引起激动剂样烟碱反应的观察结果。尼古丁的脑浓度很少增加到低-中等微摩尔浓度，据报道，该浓度可引起直接激动剂样反应，如钙内流或神经递质释放。给予人类或非人灵长类动物低微克/千克剂量的尼古丁以改善认知和工作记忆，可能只会导致低纳摩尔脑浓度，这与尼古丁诱导受体脱敏的能力更一致。在这里，我们回顾的数据表明，尼古丁，其主要代谢产物可替宁，和两种新的胆碱类似物，JWB 1 -84-1 [2-（4-（吡啶-3-基甲基）哌嗪-1-基）乙醇]和JAY 2 -22-33，JWB 1 -84-1 [2-（甲基（吡啶-3-基甲基）氨基）乙醇]，改善猕猴的工作记忆。这四种化合物在任务中的有效性是线性相关的，它们的有效性产生脱敏的升压反应引起的nAChR激动剂在大鼠神经节刺激。只有尼古丁引起激动剂样作用（增加静息血压）。因此，有可能开发新的化学实体，其具有脱敏nAChR的能力，而没有先行激动剂作用。因为这些“沉默脱敏剂”可能是变构作用，所以可以获得额外程度的亚型特异性。
The specific pharmacological response evoked by a nicotinic acetylcholine receptor ( nAChR) agonist is governed by the anatomical distribution and expression of each receptor subtype and by the stoichiometry of subunits comprising each subtype. Contributing to this complexity is the ability of agonists that bind to the orthosteric site of the receptor to alter the affinity state of the receptor and induce desensitization and the observation that, at low doses, some nAChR antagonists evoke agonist-like nicotinic responses. Brain concentrations of nicotine rarely increase to the low-mid micromolar concentrations that have been reported to evoke direct agonist-like responses, such as calcium influx or neurotransmitter release. Low micro-gram per kilogram doses of nicotine administered to humans or to nonhuman primates to improve cognition and working memory probably result only in low nanomolar brain concentrations-more in line with the ability of nicotine to induce receptor desensitization. Here we review data illustrating that nicotine, its major metabolite cotinine, and two novel analogs of choline, JWB1-84-1 [2-(4-(pyridin-3-ylmethyl)piperazin-1-yl)ethanol] and JAY2-22-33, JWB1-84-1 [2-(methyl(pyridine-3-ylmethyl)amino)-ethanol], improve working memory in macaques. The effectiveness of these four compounds in the task was linearly related to their effectiveness in producing desensitization of the pressor response to ganglionic stimulation evoked by a nAChR agonist in rats. Only nicotine evoked an agonist-like action ( increased resting blood pressure). Therefore, it is possible to develop new chemical entities that have the ability to desensitize nAChRs without an antecedent agonist action. Because these "silent desensitizers" are probably acting allosterically, an additional degree of subtype specificity could be attained.