Allosteric Modulators of Adenosine Receptors

Allosterism occurs when a ligand binds to a receptor on a binding site distinct from the orthosteric one to which endogenous ligand normally binds. Among the G protein-coupled receptors (GPCRs), the adenosine receptors (ARs), classified as A1, A2A, A2B, and A3 are the first known to be allosterically regulated. The first part of this chapter has focused on the mechanism behind the allosteric modulation on GPCRs, and specifically on ARs. To date, three main mechanisms have been recognized, namely: (1) the allosteric transition, due to the transition from the inactive to the active state; (2) the receptor dimerization; and (3) the ligand of exogenous or endogenous ligands. In the second part, an overview on the medicinal chemistry of adenosine allosteric modulators, in terms of chemical structure and structure–activity relationships, has been reported, highlighting the most outstanding advances in the development of AR modulators endowed with therapeutic potential.