Tactical Approaches to Interconverting GPCR Agonists and Antagonists
Tactical Approaches to Interconverting GPCR Agonists and Antagonists
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DOI：
10.1021/acs.jmedchem.5b00982
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发表时间：
2016-02-11
影响因子：
7.3
通讯作者：
Amin, Elizabeth Ambrose
中科院分区：
文献类型：
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作者：
Dosa, Peter I.;Amin, Elizabeth Ambrose
有许多报道的例子表明，GPCR 靶向配体的微小结构修饰导致其功能活性发生重大变化，将激动剂转化为拮抗剂，反之亦然。这些功能活性的变化通常伴随着结合亲和力的可忽略不计的变化。目前的观点侧重于概述和分析用于相互转换 GPCR 激动剂、部分激动剂和拮抗剂的各种方法，以便在具有治疗意义的 GPCR 上实现预期的功能活性。更好地了解可能改变 GPCR 配体功能活性的特定结构修饰可能有助于研究人员设计 GPCR 靶向药物和/或探针化合物，特别是在特定配体表现出良好效力但在所选 GPCR 上不具有首选功能活性的情况下。
There are many reported examples of small structural modifications to GPCR-targeted ligands leading to major changes in their functional activity, converting agonists into antagonists or vice versa. These shifts in functional activity are often accompanied by negligible changes in binding affinity. The current perspective focuses on outlining and analyzing various approaches that have been used to interconvert GPCR agonists, partial agonists, and antagonists in order to achieve the intended functional activity at a GPCR of therapeutic interest. An improved understanding of specific structural modifications that are likely to alter the functional activity of a GPCR ligand may be of use to researchers designing GPCR-targeted drugs and/or probe compounds, specifically in cases where a particular ligand exhibits good potency but not the preferred functional activity at the GPCR of choice.