Allosteric modulation of the M1 muscarinic acetylcholine receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer's disease.
Allosteric modulation of the M1 muscarinic acetylcholine receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer's disease.
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DOI：
10.1016/j.drudis.2013.09.005
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发表时间：
2013-12
影响因子：
7.4
通讯作者：
Lindsley, Craig W.
中科院分区：
文献类型：
--
作者：
Melancon, Bruce J.;Tarr, James C.;Panarese, Joseph D.;Wood, Michael R.;Lindsley, Craig W.
AMPA、NR2B、mGlu2、mGlu5和M1针对谷氨酸能功能障碍的变构调节是精神分裂症治疗的一个重要研究领域。在这些靶点中，已证明使用毒蕈碱激活剂治疗阿尔茨海默病（AD）和精神分裂症具有临床前景。这些疾病激发了研究人员确定调节前脑胆碱能传递的作用，这主要是由毒蕈碱乙酰胆碱受体（mAChR）的五种亚型之一调节的，mAChR是g蛋白偶联受体（gpcr）的一个亚家族。在这五种亚型中，M1在负责学习、认知和记忆的大脑区域高度表达。Xanomeline是一种选择性适中的正构毒蕈碱激动剂，是最早显示出改善阿尔茨海默病患者行为障碍和对精神分裂症有效的化合物之一。由于这些初步的临床结果，许多科学家，包括我们实验室的科学家，一直在努力阐明M1与化合物的作用，这些化合物通过靶向受体激活的变构模式，对M1受体表现出更高的选择性。本文将对这一领域中选定的化合物进行调查。
Allosteric modulation of AMPA, NR2B, mGlu2, mGlu5 and M1, targeting glutamatergic dysfunction, represents a significant area of research for the treatment of schizophrenia. Of these targets, clinical promise has been demonstrated using muscarinic activators for the treatment of Alzheimer’s disease (AD) and schizophrenia. These diseases have inspired researchers to determine the effects of modulating cholinergic transmission in the forebrain, which is primarily regulated by one of five subtypes of muscarinic acetylcholine receptor (mAChR), a subfamily of G-protein-coupled receptors (GPCRs). Of these five subtypes, M1 is highly expressed in brain regions responsible for learning, cognition and memory. Xanomeline, an orthosteric muscarinic agonist with modest selectivity, was one of the first compounds that displayed improvements in behavioral disturbances in AD patients and efficacy in schizophrenics. Since these initial clinical results, many scientists, including those in our laboratories, have strived to elucidate the role of M1 with compounds that display improved selectivity for this receptor by targeting allosteric modes of receptor activation. A survey of selected compounds in this area will be presented.
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DOI：
10.1038/nrd2760
发表时间：
2009-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1523/jneurosci.0337-12.2012
发表时间：
2012-06-20
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Digby GJ;Noetzel MJ;Bubser M;Utley TJ;Walker AG;Byun NE;Lebois EP;Xiang Z;Sheffler DJ;Cho HP;Davis AA;Nemirovsky NE;Mennenga SE;Camp BW;Bimonte-Nelson HA;Bode J;Italiano K;Morrison R;Daniels JS;Niswender CM;Olive MF;Lindsley CW;Jones CK;Conn PJ
通讯作者：
Conn PJ
影响因子：
13.6
作者：
Field JR;Walker AG;Conn PJ
通讯作者：
Conn PJ
影响因子：
2.7
作者：
Budzik, Brian;Garzya, Vincenzo;Jin, Jian
通讯作者：
Jin, Jian
影响因子：
5
作者：
Heinrich, Julia N.;Butera, John A.;Mayer, Scott C.
通讯作者：
Mayer, Scott C.