Positive allosteric modulation of the adenosine A2a receptor attenuates inflammation

摘要: Adenosine is produced at high levels inflamed sites as a by-product of cellular activation and breakdown. mediates its anti-inflammatory activity primarily through the adenosine A2a receptor (A2aR), member G-protein coupled receptors. A2aR agonists have demonstrated efficacy, however, their therapeutic utility hindered by lack subtype selectivity upon systemic exposure. We sought to harness effects enhancing responsiveness endogenously allosteric modulation. identified family positive modulators (PAMs) A2aR. Using one this PAM family, AEA061, we demonstrate that A2aRs are amenable enhancement such produces increased signaling diminished inflammation in vivo. was evaluated using cell-based cAMP assay. Binding affinity determined [3H]CGS 21680. A2aR-mediated quantified [35S]GTP-γS. The effect AEA061 on cytokine production primary monocytes splenocytes. LPS-induced mouse model inflammation. had no detectable intrinsic agonist towards either rat or human A2aRs. enhanced efficacy 11.5 2.8 fold respectively. also maximal response 4.2 2.1 for potentiated agonist-mediated Gα 3.7 fold. Additionally, both well Bmax 1.8 3 Consistent with role A2aR, inhibited TNF-α, MIP-1α, MIP-1β, MIP-2, IL-1α, KC RANTES LPS-stimulated macrophages and/or Moreover, reduced circulating plasma TNF-α MCP-1 IL-10 endotoxemic intact, but not deficient, mice. increases adenosine, thereby increasing potency which translates responsiveness. Since negatively regulates inflammation, PAMs offer novel means modulating inflammatory processes.