Efficacy modulation by targeting the sodium binding allosteric site in the delta opioid receptor

Abstract ID 100583 Poster Board 286 The rising prevalence of chronic pain and overdose deaths from classical opioids targeting μ opioid receptor (μOR) have fueled a need for reliable long-term analgesics, which use different targets and mechanisms. The δ opioid receptor (δOR) has been considered an attractive alternative target for non-addictive analgesics, especially for its lack of constipation and respiratory depression and effectiveness in alleviating chronic pain. However, δOR activation was found to induce seizures, precluding clinical use of full δOR agonists. Partial agonists may offer a more controlled and gradual activation of a receptor compared to full agonists, however molecular mechanism of partial agonism has remained unclear, hindering the development of such ligands. Using a structure-based approach, we explored the engagement of the sodium binding pocket in δ opioid receptor (δOR) and identified the first selective δOR partial agonist, C6-Quino. Functional studies of C6 revealed that it displayed partial agonist activity at both G protein and arrestin pathways. Its interactions with the Na⁺ pocket were confirmed in the single particle cryo-EM structure coupled with molecular dynamics simulations. Finally, C6-Quino demonstrated favorable physiological properties conferring sufficient brain permeability, oral activity, and analgesic activity in multiple chronic pain models. Notably, neither μOR related locomotion interruption and respiratory depression nor δOR related convulsions were observed at analgesic doses of C6-Quino. As a fundamentally new approach on δOR, this methodology provides a blueprint toward the development of partial agonists as safe analgesics and acts as a generic method to optimize signaling profiles of other Class A GPCR's as well.