Dualsteric GPCR targeting and functional selectivity: the paradigmatic M(2) muscarinic acetylcholine receptor.
Dualsteric GPCR targeting and functional selectivity: the paradigmatic M(2) muscarinic acetylcholine receptor.
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DOI：
10.1016/j.ddtec.2012.12.003
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发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Mohr, Klaus
中科院分区：
文献类型：
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作者：
Bock, Andreas;Mohr, Klaus
毒蕈碱型乙酰胆碱受体属于A类跨膜螺旋受体，在慢性阻塞性肺疾病、膀胱过度活动症、支气管哮喘和青光眼等多种疾病的治疗中作为重要的药物靶点。尽管进行了深入的研究，但激活或阻断特定毒蕈碱受体亚型的实验配体的发现仅对M1和M4亚型成功，但对其他亚型仍然是一项具有挑战性的任务。近年来，已经引入了同时结合乙酰胆碱结合位点（即正构位点）和变构结合位点的配体。这些所谓的双构配体由于寻址变构结合位点而显示M2亚型偏好。如最近证明的，双空间受体活化沿着明显的信号传导偏好，其遵循明确的结构偏好关系。双空间受体靶向可能代表产生功能选择性的常见策略。
Muscarinic acetylcholine receptors belong to Class Aseven transmembrane helical receptors and serve as important drug targets in the treatment of various diseases such as chronic obstructive pulmonary disease, overactive bladder, bronchial asthma and glaucoma. Despite intensive research the discovery of experimental ligands which activate or block specific muscarinic receptor subtypes has only been successful for the M1 and M4 subtypes but remains a challenging task at the other subtypes. In recent years, ligands have been introduced which bind simultaneously to the acetylcholine binding site, that is, the orthosteric site, and to an allosteric binding site. These so-called dualsteric ligands display M2 subtype preference due to the addressing of the allosteric binding site. As proven recently, dualsteric receptor activation goes along with a pronounced signaling bias which follows clear structure-bias-relationships. Dualsteric receptor targeting might represent a common strategy to generate functional selectivity.