Allosteric activators of muscarinic receptors as novel approaches for treatment of CNS disorders.
Allosteric activators of muscarinic receptors as novel approaches for treatment of CNS disorders.
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DOI：
10.1039/c002938f
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发表时间：
2010-08
影响因子：
--
通讯作者：
Conn PJ
中科院分区：
文献类型：
--
作者：
Digby GJ;Shirey JK;Conn PJ
毒蕈碱乙酰胆碱受体（mAChRs）是治疗多种中枢神经系统疾病的令人兴奋的治疗靶点。在不同的mAChR亚型之间，包含正位乙酰胆碱（ACh）结合位点的氨基酸的高度保守性阻碍了与该位点结合的亚型选择性化合物的发展。因此，许多学术界和工业界的研究人员现在都专注于开发mahrs的变构激活剂，包括正变构调节剂（pam）和变构激动剂。在过去的10年里，在发现变构配体方面取得了重大进展，与以前开发的正构配体相比，变构配体对单个mAChR亚型具有更大的选择性。这些新的mahrs变构调节剂可能为治疗许多中枢神经系统疾病如阿尔茨海默病和精神分裂症提供治疗潜力。
Muscarinic acetylcholine receptors (mAChRs) represent exciting therapeutic targets for the treatment of multiple CNS disorders. The high degree of conservation of amino acids comprising the orthosteric acetylcholine (ACh) binding site between individual mAChR subtypes has hindered the development of subtype-selective compounds that bind to this site. As a result, many academic and industry researchers are now focusing on developing allosteric activators of mAChRs including both positive allosteric modulators (PAMs) and allosteric agonists. In the past 10 years major advances have been achieved in the discovery of allosteric ligands that possess much greater selectivity for individual mAChR subtypes when compared to previously developed orthosteric agents. These novel allosteric modulators of mAChRs may provide therapeutic potential for treatment of a number of CNS disorders such as Alzheimer’s disease and schizophrenia.