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 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.

Automated summary

G protein-coupled receptors (GPCRs) are targeted by approximately one-third of FDA-approved small molecule drugs. Among the four adenosine GPCR subtypes, the adenosine A(1) receptor (A(1)R) plays important physiological roles in humans. A(1)R has been identified as a potential therapeutic target for various conditions, but the development of small molecule drugs targeting A(1)R has been limited by unwanted effects. An alternative approach using A(1)R allosteric modulators that target a different binding site shows promise in overcoming these limitations. This review provides insights into the therapeutic potential of A(1)R and recent advances in understanding its allosteric modulation.