Positive allosteric modulators of type 5 metabotropic glutamate receptors (mGluR5) and their therapeutic potential for the treatment of CNS disorders.
Positive allosteric modulators of type 5 metabotropic glutamate receptors (mGluR5) and their therapeutic potential for the treatment of CNS disorders.
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DOI：
10.3390/molecules16032097
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发表时间：
2011-03-02
期刊：
影响因子：
--
通讯作者：
Olive MF
中科院分区：
文献类型：
--
作者：
Cleva RM;Olive MF
利用选择性药理学拮抗剂或靶向基因缺失的研究已经证明，5型代谢型谷氨酸受体（mGluR5）是用于治疗中枢神经系统（CNS）的许多病症的关键介质和潜在治疗靶标，所述病症包括抑郁症、焦虑症、药物成瘾、慢性疼痛、脆性X综合征、帕金森病和胃食管反流病。然而，近年来，mGluR5受体的正变构调节剂（PAM）的开发已经揭示，该受体的变构活化也可能对治疗其他CNS疾病具有潜在的治疗益处，包括精神分裂症、与慢性药物使用相关的认知缺陷和消退学习缺陷。在这里，我们总结了各种mGluR5 PAM的发现和表征，重点是那些全身活性。我们还将回顾动物研究表明，这些分子具有潜在的疗效，作为新的抗精神病药物。最后，我们将总结表明mGluR5 PAM具有促认知作用的研究结果，例如增强突触可塑性的能力，改善各种学习和记忆任务的表现，包括消除药物寻求行为，以及逆转慢性药物使用产生的认知缺陷。
Studies utilizing selective pharmacological antagonists or targeted gene deletion have demonstrated that type 5 metabotropic glutamate receptors (mGluR5) are critical mediators and potential therapeutic targets for the treatment of numerous disorders of the central nervous system (CNS), including depression, anxiety, drug addiction, chronic pain, Fragile X syndrome, Parkinson’s disease, and gastroesophageal reflux disease. However, in recent years, the development of positive allosteric modulators (PAMs) of the mGluR5 receptor have revealed that allosteric activation of this receptor may also be of potential therapeutic benefit for the treatment of other CNS disorders, including schizophrenia, cognitive deficits associated with chronic drug use, and deficits in extinction learning. Here we summarize the discovery and characterization of various mGluR5 PAMs, with an emphasis on those that are systemically active. We will also review animal studies showing that these molecules have potential efficacy as novel antipsychotic agents. Finally, we will summarize findings that suggest that mGluR5 PAMs have pro-cognitive effects such as the ability to enhance synaptic plasticity, improve performance in various learning and memory tasks, including extinction of drug-seeking behavior, and reverse cognitive deficits produced by chronic drug use.
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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：
--
影响因子：
--
作者：
Conn, P. Jeffrey;Tamminga, Carol;Lindsley, Craig
通讯作者：
Lindsley, Craig
影响因子：
5
作者：
Hammond, Alexis S.;Rodriguez, Alice L.;Townsend, Steven D.;Niswender, Colleen M.;Gregory, Karen J.;Lindsley, Craig W.;Conn, P. Jeffrey
通讯作者：
Conn, P. Jeffrey
影响因子：
13.8
作者：
Conn PJ;Lindsley CW;Jones CK
通讯作者：
Jones CK
DOI：
10.1073/pnas.0806669105
发表时间：
2008-11-18
影响因子：
11.1
作者：
Homayoun, Hournan;Moghaddam, Bita
通讯作者：
Moghaddam, Bita