Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia

By C. Draper-Joyce, Rebecca F. Bhola, Jinan Wang, Apurba Bhattarai, A. T. Nguyen, India Cowie-Kent, Kelly O’Sullivan, Ling Yeong Chia, H. Venugopal, C. Valant and 14 more. 2021

130 citations recorded by the source corpus.

The adenosine A1 receptor (A1R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain1,2. However, development of analgesic orthosteric A1R agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects3. Here we show that [2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the A1R, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the A1R co-bound to adenosine, MIPS521 and a Gi2 heterotrimer, revealing an extrahelical lipid–detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine–receptor–G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts. MIPS521, a positive allosteric modulator of the adenosine A1 receptor, has analgesic properties in a rat model of neuropathic pain through a mechanism by which MIPS521 stabilizes the complex between adenosine, receptor and G protein.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

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Citations in the corpus

Dynamic-Backbone Protein-Ligand Structure Prediction with Multiscale Generative Diffusion Models (2022, background): “Proposing ligands that selectively target protein conformations has become an increasingly important strategy in small-molecule-based therapeutics [4–6].”