Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist

Celine Valant; Lauren T. May; Luigi AurelioChung Hui ChuoPaul J. WhiteJo-Anne BaltosPatrick M. SextonPeter J. ScammellsArthur Christopoulos

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Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist

机译：Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist

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The concepts of allosteric modulation and biased agonism are revolutionizing modern approaches to drug discovery, particularly in the field of G protein-coupled receptors (GPCRs). Both phenomena exploit topographically distinct binding sites to promote unique GPCR conformations that can lead to different patterns of cellular responsiveness. The adenosine A1 GPCR (A1AR) is a major therapeutic target for cardioprotection, but current agents acting on the receptor are clinically limited for this indication because of ontarget bradycardia as a serious adverse effect. In the current study, we have rationally designed a novel A1AR ligand (VCP746)-a hybrid molecule comprising adenosine linked to a positive allosteric modulator- specifically to engender biased signaling at the A1AR. We validate that the interaction of VCP746 with the A1AR is consistent with a bitopic mode of receptor engagement (i.e., concomitant association with orthosteric and allosteric sites) and that the compound displays biased agonism relative to prototypical A1AR ligands. Importantly, we also show that the unique pharmacology of VCP746 is (patho)physiologically relevant, because the compound protects against ischemic insult in native A1AR-expressing cardiomyoblasts and cardiomyocytes but does not affect rat atrial heart rate. Thus, this study provides proof of concept that bitopic ligands can be designed as biased agonists to promote on-target efficacy without on-target side effects.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2014年第12期|4614-4619|共6页
作者
Celine Valant; Lauren T. May; Luigi AurelioChung Hui ChuoPaul J. WhiteJo-Anne BaltosPatrick M. SextonPeter J. ScammellsArthur Christopoulos;
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作者单位

Drug Discovery Biology and Department of Pharmacology, Monash University, Parkville, VIC 3052, Australia;

Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
Separation; bitopic adenosine; receptor agonist;

Separation of on-target efficacy from adverse effects through rational design of a bitopic adenosine receptor agonist

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