Adenosine is a physiological
nucleoside which acts as an autocoid and activates
G protein-coupled membrane receptors, designated A(1), A(2A), A(2B) and A(3).
Adenosine plays an important role in many (patho)physiological conditions in the CNS as well as in peripheral organs and tissues.
Adenosine receptors are present on virtually every cell. However, receptor subtype distribution and densities vary greatly.
Adenosine itself is used as a therapeutic agent for the treatment of supraventricular
paroxysmal tachycardia and arrhythmias and as a vasodilatatory agent in cardiac imaging. During the past 20 years, a number of selective agonists for A(1), A(2A) and A(3)
adenosine receptors have been developed, all of them structurally derived from
adenosine. Several such compounds are currently undergoing clinical trials for the treatment of
cardiovascular diseases (A(1)and A(2A)),
pain (A(1)), wound healing (A(2A)),
diabetic foot ulcers (A(2A)),
colorectal cancer (A(3)) and
rheumatoid arthritis (A(3)). Clinical evaluation of some A(1) and A(2A)
adenosine receptor agonists has been discontinued. Major problems include side effects due to the wide distribution of
adenosine receptors; low brain penetration, which is important for the targeting of
CNS diseases; short half-lifes of compounds; or a lack of effects, in some cases perhaps due to receptor desensitisation or to low receptor density in the targeted tissue. Partial agonists, inhibitors of
adenosine metabolism (
adenosine kinase and deaminase inhibitors) or allosteric activators of
adenosine receptors may be advantageous for certain indications, as they may exhibit fewer side effects.