AUTHOR=Nguyen Anh T. N. , Tran Quan L. , Baltos Jo-Anne , McNeill Samantha M. , Nguyen Diep T. N. , May Lauren T. 

TITLE=Small molecule allosteric modulation of the adenosine A1 receptor

JOURNAL=Frontiers in Endocrinology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2023.1184360

DOI=10.3389/fendo.2023.1184360

ISSN=1664-2392

ABSTRACT=<p>G protein-coupled receptors (GPCRs) represent the target for approximately a third of FDA-approved small molecule drugs. The adenosine A<sub>1</sub> receptor (A<sub>1</sub>R), one of four adenosine GPCR subtypes, has important (patho)physiological roles in humans. A<sub>1</sub>R has well-established roles in the regulation of the cardiovascular and nervous systems, where it has been identified as a potential therapeutic target for a number of conditions, including cardiac ischemia-reperfusion injury, cognition, epilepsy, and neuropathic pain. A<sub>1</sub>R small molecule drugs, typically orthosteric ligands, have undergone clinical trials. To date, none have progressed into the clinic, predominantly due to dose-limiting unwanted effects. The development of A<sub>1</sub>R allosteric modulators that target a topographically distinct binding site represent a promising approach to overcome current limitations. Pharmacological parameters of allosteric ligands, including affinity, efficacy and cooperativity, can be optimized to regulate A<sub>1</sub>R activity with high subtype, spatial and temporal selectivity. This review aims to offer insights into the A<sub>1</sub>R as a potential therapeutic target and highlight recent advances in the structural understanding of A<sub>1</sub>R allosteric modulation.</p>