Adenosine receptors as drug targets

Abstract

There are four adenosine receptors, A(1), A(2A), A(2B) and A(3), together forming a defined subgroup of G protein coupled receptors. They are well conserved and widely expressed. The endogenous agonist, adenosine, has a minimal concentration in body fluids (20-200 nM) that is sufficient to slightly activate the receptors where they are very highly expressed-as in the basal ganglia, on fat cells and in the kidney. Here adenosine can play a physiological role and here antagonists such as caffeine can have effects in healthy individuals. Adenosine levels rise in stress and distress (up to 30 microM in ischemia) and tend to minimize the risk for adverse outcomes by increasing energy supply and decreasing cellular work, by stimulating angiogenesis, mediating preconditioning and having multiple effects on immune competent cells. These pathophysiological roles of adenosine also offer some potential drug targets, but the fact that adenosine receptors are involved in so many processes does not simplify drug development.

Figure 1

Schematic illustration of the relationship between adenosine concentration and the effect mediated by adenosine receptors when the receptors are very abundant (as for example the A_2A receptors on striatopallidal neurons, or when they are less abundant. This relationship is then superimposed on data on the levels of adenosine in tissue fluids under different circumstances.

Figure 2

Some of the potential uses of drugs that act as agonists (left) and antagonists (right) at the four different adenosine receptors are indicated.