Orphan G protein-coupled receptors: from DNA to drug targets

Although G protein-coupled receptors (GPCRs) are the most numerous therapeutic targets to date, ligands remain unknown for approximately two-thirds of these receptors. The challenge in the post-genomic era is to evaluate the role of these 'orphan' GPCRs in normal physiology and disease, and to develop new therapeutics based on this information. A prevalent strategy to determine the function of these orphan GPCRs is to identify specific ligands that conditionally modulate their function. These ligands can then be used to explore the role of the receptor-ligand pair in relevant models of disease. Some promise is emerging from this infant field of functional genomics as several recently deorphanized GPCRs may be potential drug targets for many diseases, including obesity, cardiovascular disease, inflammation and cancer.