Experimental challenges to targeting poorly characterized GPCRs: uncovering the therapeutic potential for free fatty acid receptors.

The G protein-coupled receptors (GPCRs) are extremely successful drug targets, with recent estimates suggesting that approximately 30% of all currently available therapeutics act at these receptors. Despite this success, only a small number of the over 400 known nonodorant GPCRs are currently targeted, suggesting there is still untapped therapeutic potential. However, as most GPCRs were identified based on their sequence homology to other members of the superfamily, many still remain "orphan" receptors without known ligands. Indeed, even once a GPCR has been deorphanized, the receptor typically is still poorly characterized in terms of its pharmacology and biological functions, presenting a unique set of experimental challenges in order to define its therapeutic potential. We discuss some of these challenges and how they have been addressed in order to uncover the therapeutic potential of five recently deorphanized receptors that are activated by short- and long-chain free fatty acids.