Grant: Operating Grant

Delta-opioid receptor agonists have demonstrated efficacy in preclinical models of pain, depression, and Parkinson's disease. However, drugs targeting this receptor induce side effects including seizures, respiratory depression, tolerance, dependence and immunosuppression, among others. Over the last decade, pharmacological concept has evolved remarkably after the finding that different ligands, at the same receptor, can selectively activate and prefer certain signalling pathways among all pathways activated by balanced ligands. This intrinsic property of ligands, known as "functional selectivity", is conferred by the differential engagement of the ligand with the receptor, leading to the notion that the fine-tuning of receptor function can be achieved through the use of functionally selective ligands. This new paradigm has opened up the way for the generation of pharmacologically distinct drugs with enhanced therapeutic potential, while reducing their deleterious side effects. We recently discovered a cavity housing a sodium ion in the core of the delta-opioid receptor. Our findings clarified observation made more than 40 years ago showing that sodium negatively regulates agonist interaction with this receptor. Our works also highlighted the unexpected role of this cavity in controlling receptor functional selectivity. These findings lead to the hypothesis that this cavity could serve as a target site to design a novel generation of drugs with reduce side effects and increase therapeutic potential. My works aim to study and understand the mechanism by which this novel cavity and the sodium ion controlled the selective activation of the receptor-signaling outcome. I also pursued the objective of looking at the druggability of this unique site with the long-term goal to design drug that will specifically target this cavity to generate novel therapeutic avenues for the treatment of debilitating disease such as pain, depression and Parkinson's disease.