Chemical biology of mGlu4 receptor activation: dogmas, challenges, strategies and opportunities.
Chemical biology of mGlu4 receptor activation: dogmas, challenges, strategies and opportunities.
复制标题
mGlu4 受体激活的化学生物学：教条、挑战、策略和机遇。
DOI：
10.2174/1568026614666140902143830
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发表时间：
2014
影响因子：
3.4
通讯作者：
D. Doller
中科院分区：
文献类型：
--
作者：
Xinyan Huang;E. Dale;R. Brodbeck;D. Doller
药物设计需要清楚地了解给定配体靶相互作用引起的表型反应。对于药物作用的经典生物靶标，这种关系相对较好地理解，但对于一些新靶标，特别是那些易于变构调节的靶标，发展这种理解可能代表更具挑战性的任务。为了了解 mGlu4 受体激活所产生的功能反应的本质，对其分子和细胞生物学进行了综述，包括所涉及的信号传导途径、中枢神经系统及其他系统中的受体定位以及与疾病的潜在遗传联系。将正构激动剂和变构调节剂的广泛持有的观点与通过正构和变构机制激活 mGlu4 受体的具体观察结果进行比较。首先，讨论了氨基酸 mGlu4 受体激动剂的亚型选择性和脑渗透，然后是功能变构效应的量化、异二聚体在功能反应中的潜在作用，以及 mGlu4 受体 PAM 的超生理功效的观察。我们表明，在我们的分析中，这些属性不同于从广泛的知识中推断出的属性。此外，还总结了 mGlu4 受体放射性配体和 PET 配体的最新进展。
Drug design necessitates a clear understanding of the phenotypic response to be elicited by a given ligandtarget interaction. This relationship is relatively well understood for classical biological targets of drug action, but for some novel targets, notably those amenable to allosteric modulation, developing such understanding may represent a more challenging task. In order to gain knowledge on the nature of the functional response derived from mGlu4 receptor activation, its molecular and cell biology are reviewed, including signalling pathways involved, receptor localization in central nervous system and beyond, and potential genetic links to disease. Broadly held views for both, orthosteric agonists as well as allosteric modulators, are compared with specific observations for the case of mGlu4 receptor activation via orthosteric and allosteric mechanisms. First, sub-type selectivity and brain penetration of amino acid mGlu4 receptor agonists are discussed, followed by the quantification of functional allosteric effects, the potential role of heterodimers in the functional response, and the observation of supra-physiological efficacy of mGlu4 receptor PAMs. We show that, in our analysis, these attributes differ from those that may be expected by extrapolating from broad knowledge. In addition, recent progress with mGlu4 receptor radioligands and PET ligands is summarized.