Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders.
Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders.
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DOI：
10.1016/j.neuron.2017.03.016
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发表时间：
2017-05-03
期刊：
影响因子：
16.2
通讯作者：
Conn PJ
中科院分区：
文献类型：
--
作者：
Foster DJ;Conn PJ
G蛋白偶联受体（GPCRs）在调节脑功能中起着关键作用。最近的进展极大地扩展了我们对这些受体作为复杂信号机器的理解，这些受体可以采用多种构象并调节多个下游信号通路。虽然激动剂和拮抗剂传统上被用于靶向GPCR，但变构调节剂提供了几种机制优势，包括区分密切相关的受体亚型的能力。最近，发现了赋予偏性并调节一些但不是全部给定受体的下游信号传导途径的变构配体，可以提供具有显著精度的脑回路的药理学调节。此外，已经开发了具有前所未有的特异性的变构调节剂，其可以基于受体的二聚化状态区分给定受体亚型的亚群。这些进展不仅提供了对特定受体群体的生物学作用的深入了解，而且为治疗许多CNS疾病带来了巨大的希望。
G-protein coupled receptors (GPCRs) play critical roles in regulating brain function. Recent advances have greatly expanded our understanding of these receptors as complex signaling machines that can adopt numerous conformations and modulate multiple downstream signaling pathways. While agonists and antagonists have traditionally been pursued to target GPCRs, allosteric modulators provide several mechanistic advantages including the ability to distinguish between closely related receptor subtypes. Recently, the discovery of allosteric ligands that confer bias and modulate some, but not all, of a given receptor's downstream signaling pathways can provide pharmacological modulation of brain circuitry with remarkable precision. In addition, allosteric modulators with unprecedented specificity have been developed that can differentiate between subpopulations of a given receptor subtype based on the receptor's dimerization state. These advances are not only providing insight into the biological roles of specific receptor populations, but hold great promise for treating numerous CNS disorders.