Objective

G protein-coupled receptors (GPCRs) couple to G proteins but also other cellular proteins such as arrestins. It was originally thought that GPCR interaction with arrestins led solely to GPCR desensitization. It is now known that arrestins, apart from uncoupling the GPCR from G protein, also lead to GPCR internalization as well as arrestin-dependent cellular signalling. Biased ligands activate the receptor but signal predominantly via G protein or arrestin, compared to “balanced” ligands which signal effectively through both pathways. The therapeutic potential of biased ligands is enormous, as such ligands could for example, produce therapeutic effects but avoid adverse effects. In the instance of the mu opioid receptor, the potential is that biased ligands could produce effective analgesia, but avoid adverse effects such as respiratory depression and constipation. In my presentation, I will discuss the concept of bias at mu and delta opioid receptors, and will discuss recent molecular and in vivo evidence obtained by ourselves and others with biased agonist drugs at these receptors. I will mention problems with assessing bias in vitro and the challenges of moving studies on from in vitro cell expression studies to the in vivo situation. In particular I will address the question of whether ligand bias is likely to fulfil the promise of producing more targeted and effective drugs in the future.