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Endocrinol."],"abstract":"<jats:p>G protein-coupled receptors (GPCRs) represent the target for approximately a third of FDA-approved small molecule drugs. The adenosine A<jats:sub>1<\/jats:sub> receptor (A<jats:sub>1<\/jats:sub>R), one of four adenosine GPCR subtypes, has important (patho)physiological roles in humans. A<jats:sub>1<\/jats: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<jats:sub>1<\/jats: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<jats:sub>1<\/jats: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<jats:sub>1<\/jats:sub>R activity with high subtype, spatial and temporal selectivity. This review aims to offer insights into the A<jats:sub>1<\/jats:sub>R as a potential therapeutic target and highlight recent advances in the structural understanding of A<jats:sub>1<\/jats:sub>R allosteric modulation.<\/jats:p>","DOI":"10.3389\/fendo.2023.1184360","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T10:48:29Z","timestamp":1687776509000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Small molecule allosteric modulation of the adenosine A1 receptor"],"prefix":"10.3389","volume":"14","author":[{"given":"Anh T. 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