Biased agonism at the mu opioid receptor has been sought to improve opioid-mediated pain relief while avoiding adverse side effects. In particular, agonists that show a relative improvement in their ability to promote G protein signaling over barrestin2 recruitment to MOR have been sought, and reported by many different groups.  We have developed a class of these agonists that display a wide spectrum of bias; some agonists impart preferential signaling to G proteins, while some induce preferential recruitment of barrestin2. Recently, we reported that some of the G protein signaling biased agonists are also tight binding, non-competitive agonists.  This class of compounds, having wide ranging pharmacological properties, including partial and full efficacy agonists, will help us understand which properties may be best predictive of improved therapeutic outcomes.  Moreover, they will help us understand, from a mechanistic perspective, of what causes the receptor to appear to prefer certain interactions over others.  

Funding is from NIDA (5R01DA033073, R01DA038964, F32DA052124 (Agnes Acevedo-Canabal).