Probing the orphan receptors: Tools and directions

The endogenous ligands activating a large fraction of the G Protein Coupled Receptor (GPCR) family members have yet to be identified. These receptors are commonly labeled as orphans (oGPCRs), and because of the absence of available pharmacological tools they are currently understudied. Nonetheless, genome wide association studies, together with research using animal models identified many physiological functions regulated by oGPCRs. Similarly, mutations in some oGPCRs have been associated with rare genetic disorders or with an increased risk of developing pathologies. The once underestimated pharmacological potential of targeting oGPCRs is increasingly being exploited by the development of novel tools to understand their biology and by drug discovery endeavors aimed at identifying new modulators of their activity. Here, we summarize recent advancements in the field of oGPCRs and future directions.