Friday, May 10, 2024
5/10/2024
ABSTRACT Opioid use disorders (OUD) are responsible for a major health and socioeconomic crisis in the US, resulting in more than $500B burden on the economy and 75,673 deaths in the year leading up to April, 2021. More than 80% of OUD cases began with the use of prescription opioid painkillers, which remain in use due to their efficacy in treating severe pain. The current clinically-used analgesics target the mu opioid receptor (MOR), which also produces of liabilities of dependence and addiction leading to OUD, and potentially lethal respiratory depression. Poorly treated pain and diversion and misuse of prescription opioid drugs are key contributors to the worsening opioid epidemic. Development of new safe and effective analgesics with diminished addiction and abuse potential is desperately needed to reduce usage of MOR agonist-based analgesics which promote OUD. We propose to target the sodium site in the delta opioid receptor (DOR) as a novel mechanism to develop pain relievers devoid of the adverse effects associated with MOR agonist analgesics. We propose to use a bitopic ligand strategy, generating novel DOR agonists binding to both the conventional orthosteric site and the sodium site in the DOR. Emerging evidence suggests these novel bitopic DOR ligands produce analgesia but lack the seizure phentotype associated with first generation DOR agonists limited to targeting the orthosteric site of DOR. Our main goal is establish a relationship between DOR efficacy and potency at G-protein and arrestin signaling pathways with binding of the ligands within the sodium site. Our intial bitopic design, C6-quino, is validated by cryoEM structures suggesting that binding in the sodium site leads to partial agonism and a unique functional selectivity away from arrestin pathway signaling over known DOR agonists binding solely to the orthosteric site. To the best of our knowledge, probes with partial agonism at DOR are rare and their effects on DOR-mediated analgesia and other adverse effects are currently not well established. Our current lead has optimal in vitro ADME properties with favorable protein binding and metabolic stability, lacks the typical DOR mediated seizures and other CNS adverse effects while ameliorating allodynia in a neuropathic pain model. Our central hypothesis postulates that targeting the allosteric sodium site in conjunction with the orthostric site by diversification of DOR bitopics guided by cryoEM-enabled SAR approaches will lead to safer analgesics effective against chronic pain. Preliminary evidence suggests probes synthesized will also lack the typical side- effects associated with both DOR as well as clinically used MOR agonists. Using structure based design, we will further optimize our current lead for DOR subtype selectivity (1000x selective), in vitro potency (with DPPDE-like potency of G-protein activation) and in vivo DOR potency (seeking analgesia at ~5-10 mg/kg, s.c. or p.o.) to design our next generation bitopics. Attempts will also be made to enhance brain penetration and CNS activity by swapping the charged guanidino group. These goals will be accomplished by an interdisciplinary team with synergistic experience in medicinal chemistry, computational chemistry, structural biology and pharmacology.
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