Chapter 1 - Adenosine Receptor Biology in the Central Nervous System

Abstract

The basic pharmacology of the four adenosine receptors (A1, A2A, A2B, A3) is understood in considerable detail. Mice deficient in each individual receptor have been generated and their study has led to surprising insights, e.g., that the presence of the A2A receptor aggravates ischaemia-induced neuronal damage. From the perspective of drug development, it is reassuring to learn that each individual receptor can be deleted without affecting viability of the resulting mice. Thus, it is safe to target these receptors with antagonists. In fact, several clinical trials have recently been conducted to explore the use of agonists and antagonists in diseases and disorders, where a beneficial effect was to be expected based on the study of adenosine receptor biology. Two brain disorders stand out, because addressing adenosine receptors may be of therapeutic interest. Firstly, Parkinson’s disease, where an antagonist (istradefylline) was successfully developed to receive market approval in Japan. Secondly, a polymorphism in the A2A receptor modifies the age of onset in Huntington’s disease. Hence, it may be of interest to also target the receptor in order to treat Huntington’s disease. This requires that the role of the A2A receptor be understood.