Investigational A₃ adenosine receptor targeting agents

Adenosine is an endogenous nucleoside that accumulates in the extracellular space in response to metabolic stress and cell damage. Extracellular adenosine is a signaling molecule that signals by activating four GPCRs: the A(1), A(2A), A(2B) and A(3) receptors. Since the discovery of A(3) adenosine receptors, accumulating evidence has identified these receptors as potential targets for therapeutic intervention.

A(3) adenosine receptors are expressed on the surface of most immune cell types, including neutrophils, macrophages, dendritic cells, lymphocytes and mast cells. A(3) adenosine receptor activation on immune cells governs a broad array of immune cell functions, which include cytokine production, degranulation, chemotaxis, cytotoxicity, apoptosis and proliferation. In accordance with their multitudinous immunoregulatory actions, targeting A(3) adenosine receptors has been shown to impact the course of a wide spectrum of immune-related diseases, such as asthma, rheumatoid arthritis, cancer, ischemia and inflammatory disorders.

Given the existence of both preclinical and early clinical data supporting the utility of A(3) adenosine receptor ligands in treating immune-related diseases, further development of A(3) adenosine receptor ligands is anticipated.