Small molecule allosteric modulation of the adenosine A1 receptor

Anh T N Nguyen; Quan L Tran; Jo-Anne Baltos; Samantha M McNeill; Diep T N Nguyen; Lauren T May

doi:10.3389/fendo.2023.1184360

Small molecule allosteric modulation of the adenosine A₁ receptor

Front Endocrinol (Lausanne). 2023 Jun 26:14:1184360. doi: 10.3389/fendo.2023.1184360. eCollection 2023.

Authors

Anh T N Nguyen¹, Quan L Tran¹, Jo-Anne Baltos¹, Samantha M McNeill¹, Diep T N Nguyen², Lauren T May¹

Affiliations

¹ Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
² Department of Information Technology, Faculty of Engineering and Technology, Vietnam National University, Hanoi, Vietnam.

Abstract

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.

Keywords: A1 receptor; G protein-coupled receptor; adenosine; allosteric modulation; structure-activity relationship; structure-function relationship.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Adenosine
Binding Sites
Cognition*
Heart
Humans
Ligands
Receptor, Adenosine A1*

Substances

Adenosine
Ligands
Receptor, Adenosine A1

Grants and funding

Research on adenosine receptor signaling in Dr May’s lab was supported by a National Heart Foundation Future Leader Fellowship (101857) and National Health and Medical Research Council (Australia) project grant: APP1147291. Ongoing research into adenosine receptor signaling is supported by NHMRC Ideas grant APP2013629 and a Department of Health and Aged Care (MRFF) Stem Cell Therapies Mission grant (MRF2015957).