Adenosine and adenosine receptors: Newer therapeutic perspective

Abstract

Adenosine, a purine nucleoside has been described as a 'retaliatory metabolite' by virtue of its ability to function in an autocrine manner and to modify the activity of a range of cell types, following its extracellular accumulation during cell stress or injury. These effects are largely protective and are triggered by binding of adenosine to any of the four adenosine receptor subtypes namely A1, A2a, A2b, A3, which have been cloned in humans, and are expressed in most of the organs. Each is encoded by a separate gene and has different functions, although overlapping. For instance, both A1 and A2a receptors play a role in regulating myocardial oxygen consumption and coronary blood flow. It is a proven fact that adenosine plays pivotal role in different physiological functions, such as induction of sleep, neuroprotection and protection against oxidative stress. Until now adenosine was used for certain conditions like paroxysmal supraventricular tachycardia (PSVT) and Wolff Parkinson White (WPW) syndrome. Now there is a growing evidence that adenosine receptors could be promising therapeutic targets in a wide range of conditions including cardiac, pulmonary, immunological and inflammatory disorders. After more than three decades of research in medicinal chemistry, a number of selective agonists and antagonists of adenosine receptors have been discovered and some have been clinically evaluated, although none has yet received regulatory approval. So this review focuses mainly on the newer potential role of adenosine and its receptors in different clinical conditions.

Keywords: Anaesthesia and critical care; Parkinson's disease; asthma; epilepsy; inflammatory bowel diseases; ischaemia/reperfusion injury; refractory primary pulmonary hypertension.

Figure 1

Metabolism of adenosine. ATP, adenosine triphosphate; ADP, adenosine diphosphate; AMP, adenosine monophosphate. Modulating various enzymes/transporters will increase endogenous adenosine concentrations

Figure 2

Schematic diagram of the mechanism involved in adenosine-induced bronchoconstriction. Once generated, adenosine activates the adenosine A_2b receptors on mast cells. Upon activation of A_2b receptors, various inflammatory mediators that induce bronchoconstriction are released. ADP = adenosine diphosphate: AMP = adenosine monophosphate; ATP = adenosine triphosphate; NT = nucleotidase; NTPD= nucleoside triphosphate diphosphohydrolase.

Figure 3

Biosynthesis and catabolism of adenosine under normal conditions (A) or in the presence of inflammation (B). Endo-ADA: endo-adenosine deaminase; Ecto-ADA: ecto-adenosine deaminase; ATP: adenosine triphosphate; ADP: adenosine diphosphate; AMP: adenosine monophosphate; AK: adenosine kinase; SAH: S-adenosylhomocysteine; SAM: S-adenosylmethionine; CD73/Ecto-5-N: ecto-5-nucleotidase; Endo-5-N: endo-5-nucleotidase; NT: nucleoside transporter.