Novel GPCR paradigms at the mu-opioid receptor

Opioids, such as morphine, are the most clinically useful class of analgesic drugs for the treatment of acute and chronic pain. However, the use of opioids is greatly limited by the development of severe adverse side effects. Consequently drug discovery efforts have been directed towards improving the therapeutic profile of opioid-based treatments. Opioid receptors belong to the family of G protein-coupled receptors (GPCRs). As such the recent GPCR paradigms of biased agonism and allosterism may provide novel avenues for more effective analgesics. Biased agonism (or functional selectivity) has been described for all the opioid receptor family members. Furthermore, the first class of allosteric modulators of opioid receptors has very recently been described. However, identification and quantification of biased agonism in a manner that is informative to medicinal chemists and drug discovery programs still remains a challenge. In this review we examine the progress to date towards identification and quantification of biased agonism and allosterism at the MOR in the context of its implications for the discovery of better and safer analgesics.