Adenosine receptors as drug targets--what are the challenges?

Abstract

Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors--either directly or indirectly--have now entered the clinic. However, only one adenosine receptor-specific agent--the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma)--has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges.

Figure 1. Local amplification of adenosine signalling in response to insults or hypoxia

Under physiological conditions (upper panel), the extracellular concentration of adenosine is the sum of many biological processes, excluding intracellular adenosine production. Adenosine is transported via equilibrative nucleoside transporter 1 (ENT1) and other transporters. ATP is released via multiple processes. ATP is converted to adenosine by ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1; also known as CD39) and ecto‑5′-nucleotidase (NT5E; also known as CD73). Adenosine is metabolized to inosine, AMP or S-adenosylhomocysteine (SAH). Many cell types perform all the biological processes displayed in the figure, but some cells show only a limited repertoire. Under pathological conditions (lower panel), local adenosine signalling is markedly amplified in response to insults and hypoxia by a surge in extracellular adenosine concentration from the baseline (20-300 nM) to up to 30 μM in ischaemic or hypoxic tissues. There is also a parallel marked induction of enzymes that are responsible for ATP-dependent adenosine signalling as well as adenosine receptor expression (particularly A_2A and A_2B adenosine receptors) and the suppression of enzymes involved in adenosine metabolism, such as adenosine kinase (AK). Adenosine signalling under pathological conditions is controlled by the following factors: increased extracellular adenosine levels by ATP release; induction of ENTPD1 expression by the transcription factor SP1 and of NT5E expression by hypoxia-inducible factor-1α (HIF1α); induction of A_2A receptor expression by HIF2α and of A_2B receptor expression by HIF1α; repression of AK by HIF1α and suppression of ENT1 or ENT2 activity by HIF1α. ADA, adenosine deaminase; cAMP, cyclic AMP; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; PKA, protein kinase A.