Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators.
Pharmacological modulation of NMDA receptor activity and the advent of negative and positive allosteric modulators.
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DOI：
10.1016/j.neuint.2012.01.004
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发表时间：
2012-09
影响因子：
4.2
通讯作者：
Jane, David E.
中科院分区：
文献类型：
--
作者：
Monaghan, Daniel T.;Irvine, Mark W.;Costa, Blaise Mathias;Fang, Guangyu;Jane, David E.
关键词：
众所周知，L谷氨酸受体家族在中枢神经系统功能以及在各种神经病理和精神疾病中发挥着不同的作用。直到最近，可用于药理学调节NMDAR功能的药物类型在作用机制和亚型选择性方面都相当有限。在过去的两年里，这种情况发生了重大变化。本综述的目的是总结目前可用于调节NMDAR活性的许多药物类别。以前，这包括L-谷氨酸和甘氨酸结合位点的竞争性拮抗剂，高亲和力和低亲和力的通道阻滞剂，以及GluN2B选择性N-末端结构域结合位点拮抗剂。最近，我们和其他人发现了一类新的NMDAR试剂，它们要么是正变构调节剂，要么是负变构调节剂(分别是PAM和NAMS)。这些化合物包括PAN增强剂UBP646、GluN2A选择性增强剂/GluN2C和GluN2D抑制剂UBP512、GluN2D选择性增强剂UBP551、GluN2C/GluN2D选择性增强剂CIQ以及新的NMDAR-NAMS，如PAN抑制剂UBP618、GluN2C/GluN2D选择性抑制剂QZN46和GluN2A抑制剂UBP608和TCN201。这些新试剂不结合在L-谷氨酸或甘氨酸结合部位、离子通道孔或N-末端调节域内。总的来说，这些新的变构调节剂似乎作用于NMDAR复合体上的多个新位点。重要的是，这些药物表现出更好的亚型选择性，作为NMDAR PAM和NAMS，它们代表了新一代潜在的NMDAR疗法。
The NMDA receptor (NMDAR) family of L-glutamate receptors are well known to have diverse roles in CNS function as well as in various neuropathological and psychiatric conditions. Until recently, the types of agents available to pharmacologically regulate NMDAR function have been quite limited in terms of mechanism of action and subtype selectivity. This has changed significantly in the past two years. The purpose of this review is to summarize the many drug classes now available for modulating NMDAR activity. Previously, this included competitive antagonists at the L-glutamate and glycine binding sites, high and low affinity channel blockers, and GluN2B-selective N-terminal domain binding site antagonists. More recently, we and others have identifed new classes of NMDAR agents that are either positive or negative allosteric modulators (PAMs and NAMs, respectively). These compounds include the pan potentiator UBP646, the GluN2A-selective potentiator/GluN2C & GluN2D inhibitor UBP512, the GluN2D-selective potentiator UBP551, the GluN2C/GluN2D-selective potentiator CIQ as well as the new NMDAR-NAMs such as the pan-inhibitor UBP618, the GluN2C/GluN2D-selective inhibitor QZN46 and the GluN2A inhibitors UBP608 and TCN201. These new agents do not bind within the L-glutamate or glycine binding sites, the ion channel pore or the N-terminal regulatory domain. Collectively, these new allosteric modulators appear to be acting at multiple novel sites on the NMDAR complex. Importantly, these agents display improved subtype-selectivity and as NMDAR PAMs and NAMs, they represent a new generation of potential NMDAR therapeutics.
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DOI：
10.1002/neu.480230915
发表时间：
1992-11-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
CHOI, DW
通讯作者：
CHOI, DW
影响因子：
5.5
作者：
Chen, Philip E.;Geballe, Matthew T.;Wyllie, David J. A.
通讯作者：
Wyllie, David J. A.
影响因子：
4.7
作者：
Costa, Blaise Mathias;Irvine, Mark W.;Monaghan, Daniel T.
通讯作者：
Monaghan, Daniel T.
影响因子：
5.3
作者：
Berberich, S;Punnakkal, P;Köhr, G
通讯作者：
Köhr, G
影响因子：
16.2
作者：
Armstrong, N;Gouaux, E
通讯作者：
Gouaux, E