Abstract
Target-based G protein-coupled receptors (GPCRs) drug discovery has historically focused on the development of ligands that either activate or inhibit the signal response of one specific receptor. However, the potential benefits of ligands with multi-target activity have gained more attention, particularly for the development of drugs for complex diseases such as CNS disorders. Furthermore, GPCRs have traditionally been studied in isolation, whereas there is increased evidence of GPCRs existing in dimeric and higher-order oligomeric complexes. These aspects have contributed to the development of a range of novel ligand types, which are able to interact with multiple GPCR monomers, including dual-acting ligands and prodrugs as well as homo- and heterobivalent ligands. This chapter provides an overview on the development of ligands with multi-target activity against at least one receptor subtype of the purinergic receptor family. In addition to summarising reported bifunctional ligands in this field, the important design aspects and the role of computational methods and structural biology in guiding the development of bifunctional ligands are discussed.