GPCRs represent the largest cell surface receptor family, regulating all physiological functions and thus constitute major drug targets. Until recently, the receptor was believed to work as an ON-OFF switch able to promote activation of all signaling cascades associated with this receptor. The new concept of biased agonism led recently to the notion of functional selectivity of ligands favoring the activation of specific signaling pathways, thus paving the way for developing pathway-specific drugs with increased efficacy and decreased side effects. However, recent publication of new biosensors with high sensitivity probing the first signaling events close to the active receptor and combined with the analysis of the activation of more downstream effectors has challenged the definition of biased agonism. This review highlights the importance of discriminant functional assays for biased ligands screening and the future strategies for pharmacological mapping optimization aiming to select new drugs with enhanced therapeutic effects.
© 2012 médecine/sciences – Inserm / SRMS.