A3 Receptor Ligands: Past, Present and Future Trends

Abstract

The A(3) adenosine receptors (A(3) ARs), belonging to the adenosine receptor family of G-protein-coupled receptors (GPCRs), are ubiquitously expressed in a wide variety of tissues in human body, with high levels in peripheral organs and low levels in the brain. The A(3) ARs are involved in a variety of important patho-physiological processes, including modulation of cerebral and cardiac ischemic damage, inflammation, modulation of intraocular pressure, regulation of normal and tumor cell growth, and immunosuppression. Consequently, A(3) AR selective ligands may represent important pharmacological tools in the treatment of a variety of diseases. Indeed, the development of potent and selective A(3) AR ligands has been the subject of medicinal chemistry research for more than two decades. Although to date a considerable number of selective A(3) AR agonists and antagonists have been discovered, much is still to be learned about the exact function of this subtype, due to its enigmatic role in several physiological processes. In the last two decades, numerous medicinal chemistry groups have made intense efforts in searching for ideal ligands for the A(3) AR subtype. The purpose of this review is to summarize the most recent developments made in the field of selective A(3) AR ligands, which have been subdivided on the basis of their main chemical structural features. For each chemical class, attention has been focused on the SARs which determine ligand affinity and selectivity for the target subtype, and on eventually available preclinical data.

A3 Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy

“…For example, an A 3 AR upregulation has been found in human colorectal and hepatocellular carcinomas that was reflected in peripheral blood cells, thus making this AR subtype a possible marker for cancer, reflecting receptor status in remote tumor tissue . As for the role of A 3 AR in tumors, pro‐ and antiproliferative effects due to their activation have been documented in several cancer cell types . A 3 AR activation decreased prostate cancer cell migration in vitro and in vivo and inhibited cell proliferation, inducing G1 cell cycle arrest and apoptosis …”

“…Several xanthine or purine analogues were examined first, but none showed significant affinity or selectivity at rat A 3 AR. 96,100,144,145 Consequently, different classes of compounds, that could be classified as nonxanthine derivatives 135,[144][145][146][147][148][149] and the lately nucleoside-derived antagonists, have been discovered as highly potent and selective A 3 AR antagonists.…”

“…[87][88][89] As for the role of A 3 AR in tumors, pro-and antiproliferative effects due to their activation have been documented in several cancer cell types. 69,74,75,[298][299][300][301][302][303][304][305][306][307] A 3 AR activation decreased prostate cancer cell migration in vitro and in vivo and inhibited cell proliferation, inducing G1 cell cycle arrest and apoptosis. 70,73,308 Even though contrasting results about the role of A 3 AR agonists and antagonists in cancer still are present in literature data, only the therapeutic utility of A 3 AR agonists has been supported by in vivo studies.…”

Controlling murine and rat chronic pain through A 3 adenosine receptor activation

“…The clinical use of adenosine in pain is underscored by the findings that intrathecal delivery provides long‐lasting relief in patients with chronic pain (12). Although selective A 1 AR and A 2A AR agonists are in clinical development for neuropathic pain (11, 12, 14), but their use is restricted to local delivery. Systemic administration would risk cardiovascular side effects from activation of the A 1 AR expressed in conducting tissues or A 2A AR in vascular smooth muscle (12).…”

Networking in Autism: Leveraging Genetic, Biomarker and Model System Findings in the Search for New Treatments

“…Indeed, early investigators questioned whether A3ARs exist in the brain at all (Rivkees et al, 2000). However, more recent efforts have established clear actions of A3AR agonists in protection of the CNS against hypoxia/ischemic and inflammatory insults (Borea et al, 2009;Haas and Selbach, 2000;Taliani et al, 2010), as well as support for synaptic signaling and plasticity (Brand et al, 2001;Costenia et al, 2001;Dunwiddle et al, 1997;Macek et al, 1998).…”