Small molecule allosteric modulation of the adenosine A1 receptor
Thi Nguyen, Quan Le Tran, Jo‐Anne Baltos, Samantha M. McNeill, Diep Thi Ngoc Nguyen, Lauren T. May
Abstract
G protein-coupled receptors (GPCRs) represent the target for approximately a third of FDA-approved small molecule drugs. The adenosine A 1 receptor (A 1 R), one of four adenosine GPCR subtypes, has important (patho)physiological roles in humans. A 1 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 1 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 1 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 1 R activity with high subtype, spatial and temporal selectivity. This review aims to offer insights into the A 1 R as a potential therapeutic target and highlight recent advances in the structural understanding of A 1 R allosteric modulation.