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The epidemic of opioid abuse caused more than 47,600 deaths in 2017 alone, ( Overdose Death Rates, 2019) making drug overdose the leading cause of accidental death in the US. As the use of opioid analgesics increased and then came under greater restrictions, so too has their diversion, misuse, and switch to illicit opioids, as ~80% of opioid addicts reported initiating their habit through prescription opioids. Drugs targeting MOR are effective analgesics, but they retain high addiction potential and cause potentially lethal side effects including respiratory depression. Pain affects almost every person at some point in their lives, and it has been estimated that more than 25 million people in the United States suffer daily from severe pain ( Nahin, 2015). The findings validate a novel structure-inspired paradigm for achieving beneficial in vivo profiles for analgesia through different mechanisms that include bias, partial agonism, and dual MOR/KOR agonism.

The lead compounds, MP1207 and MP1208, displayed MOR/KOR Gi-partial agonism with diminished arrestin signaling, showed efficient analgesia with attenuated liabilities, including respiratory depression and conditioned place preference and aversion in mice. Analysis of structure-activity relationships for new MP1104 analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) as key for modulation of arrestin recruitment to both MOR and KOR. Here, we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with MP1104, to rationally design novel mixed mu (MOR) and kappa (KOR) opioid receptor agonists with reduced arrestin signaling. Department of Anesthesiology, Rutgers New Jersey Medical School, New Jersey, United States Ĭontrolling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics however, the structural determinants conferring functional selectivity are not well understood.Department of Pharmacodynamics, University of Florida, United States.Division of Molecular Therapeutics, New York State Psychiatric Institute and Departments of Psychiatry, Pharmacology, Columbia University Vagelos College of Physicians & Surgeons, United States.Department of Quantitative and Computational Biology, Department of Chemistry, Bridge Institute, Michelson Center for Convergent Bioscience, University of Southern California, United States.Department of Anesthesiology, Washington University in St.Louis College of Pharmacy and Washington University School of Medicine, United States

Department of Pharmacology, University of North Carolina, United States.

Department of Neurology and Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, United States.

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