[en] G protein-coupled receptors (GPCRs) are usually highlighted as being both the largest
family of membrane proteins and the most productive source of drug targets. However, most of
the GPCRs are understudied and hence cannot be used immediately for innovative therapeutic
strategies. Besides, there are still around 100 orphan receptors, with no described endogenous
ligand and no clearly defined function. The race to discover new ligands for these elusive
receptors seems to be less intense than before. Here, we present an update of the various
strategies employed to assign a function to these receptors and to discover new ligands. We focus
on the recent advances in the identification of endogenous ligands with a detailed description of
newly deorphanized receptors. Replication being a key parameter in these endeavors, we also
discuss the latest controversies about problematic ligand-receptor pairings. In this context, we
propose several recommendations in order to strengthen the reporting of new ligand-receptor
pairs.
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