Allosteric modulators for adenosine receptors: an alternative to the orthosteric ligands

Adenosine is a ubiquitous homeostatic substance which exerts its action by triggering four different cell membrane G protein-coupled receptors, classified as A(1), A(2A), A(2B), and A(3). Being widely distributed and deeply involved in several physiological functions, as well as pathological disorders, these receptors represent an excellent drug target and the development of specific ligands has been tested as a promising therapeutic concept. Among the obtainable ligands, allosteric modulators offer higher advantages with respect to classical orthosteric compounds, as they possible to achieve greater selectivity and better modulatory control at disease mediating receptors. Actually, synergizing with adenosine bound to the primary binding site, these compounds may modify receptor functions through interaction with an additional binding site. As a consequence, their actions depend directly on the release of the endogenous agonist. A number of compound have been developed as effective allosteric modulators. Most of them target adenosine A(1) and A(3) receptor subtypes as, to date, little or no research attempt have been made to improve the field of A(2A) and A(2B) ligands. This review updates literature on the allosteric modulators that has appeared in the last few years, focusing its attention on medicinal chemistry, in terms of chemical structure and structure-activity relationships. This will provide new perspectives on existing data and an exciting starting point for the development of novel and more effective modulators.