Morphine and other clinically used opioid agonists that target the mu-opioid receptor (MOR) remain the preferred treatment of moderate to severe pain. Drugs targeting MOR are effective analgesics when used appropriately, but are highly addictive, lead to tolerance, and are lethal when overdosed due to respiratory depression. As the use of opioid painkillers has increased, so has their misuse and transition to illicit opioids, with about 80% of addicts reported initiating their habit through prescription opioids. The epidemic of opioid abuse has caused more than 47,600 deaths in 2017 alone, making drug overdose the leading cause of accidental death in US. As effective analgesics are essential to minimize pain and suffering of many diseases, the identification of safer analgesics with diminished side effects and abuse potential is critical for breaking the vicious cycle fueling the current problem. Accordingly, the generation of safe and abuse-free opioid analgesics represents a long-standing and highly significant scientific challenge. Controlling 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. We had previously developed a morphinan based ligand named MP1104 which showed picomolar affinity at kappa opioid receptor (ACS Chem Neuro 2015, PMID: 26325040). This compound eventually led to the crystal structure of the active state of kappa opioid receptor (Cell 2018, PMID: 29307491). We now report the rational design of novel mixed MOR/KOR agonists with reduced G-protein intrinsic efficacy utilizing the active state structures of KOR and MOR. Analysis of structure-activity relationships for new MP1104 analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) and ring-C of morphinan template taking the chair conformation as key for modulation of this activity. 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. The findings validate a novel structure-inspired paradigm for achieving beneficial in vivo profiles for analgesia through different mechanisms that include, partial agonism, and dual MOR/KOR agonism.

Ring C-chair and boat conformation of morphinan template dictates functional selectivity at opioid receptors

ACS Fall 2021

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