Small molecule allosteric modulation of the adenosine A₁ receptor

G protein-coupled receptors (GPCRs) represent the target for approximately a third of FDA-approved small molecule drugs. The adenosine A₁ receptor (A₁R), one of four adenosine GPCR subtypes, has important (patho)physiological roles in humans. A₁R 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. A₁R 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 A₁R 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 A₁R activity with high subtype, spatial and temporal selectivity. This review aims to offer insights into the A₁R as a potential therapeutic target and highlight recent advances in the structural understanding of A₁R allosteric modulation.