Biased agonism at G protein-coupled receptors.

G protein-coupled receptors (GPCRs) represent the largest family of approved therapeutic targets. Ligands stimulating these receptors specifically activate multiple signalling pathways that induce not only the desired therapeutic response, but sometimes untolerated side effects that limit their clinical use. The diversity in signalling induced by each ligand could be considered a viable path for improving this situation. Biased agonism, which offers the promise of identifying pathway-selective drugs has been proposed as a means to exploit this opportunity. However, identifying biased agonists is not an easy process and quantifying ligand bias for a given signalling pathway requires careful consideration and control of several confounding factors. To date, the molecular mechanisms of biased signalling remain unclear and known theories that constitute our understanding of the mechanisms underlying therapeutic and side effects are still being challenged, making the strategy of selecting promising potential drugs more difficult. This special issue summarizes the latest advances in the discovery and optimization of biased ligands for different GPCRs. It also focuses on identifying novel insights into the field of biased agonism, while at the same time, highlighting the conceptual and experimental limitations of that concept for drug discovery. This aims to broaden our understanding of the signalling induced by the various identified biased agonists and provide perspectives that could straighten our path towards the development of more effective and tolerable therapeutics.