Mu opioid peptide (MOP) receptor agonists such as morphine and fentanyl are the most widely used analgesics for pain management. However, MOP receptor agonist-induced respiratory depression and mortality lead to mounting medical and economic burdens in the global community. Recent evidence indicates that biased MOP receptor agonists with preferred G protein activation retained analgesic effects, but they produced wider therapeutic windows. Such G protein signaling-biased MOP receptor agonists have not been systemically studied in non-human primate (NHP) models with translational potential. In this application, we select a newly discovered G protein signaling-baised MOP receptor agonist with the highest bias factor, SR-17018, which will be synthesized by Dr. Yanan Zhang at Research Triangle Institute. A series of NHP experiments will be conducted to evaluate behaivoral and physiological effects of SR-17018 in side-by-side comparisons with clinically used MOP receptor agonists following acute and repeated administration. These NHP assays have been designed specifically to reflect the therapeutic (analgesia) and side effects (respriatory depression, abuse potential, constipation, physical dependence, and tolerance) of opioid analgesics. The possibility that biased MOP receptor agonists which do not recruit beta-arrestin may be safer and have a wider therapeutic window encourages our pharmacological studies of SR-17018 in NHP models. Our unique set of behavioral and physiological assays in awake, behaving rhesus monkeys, in combination with the availability of a novel, highly G protein-biased MOP receptor agonist, SR-17018, sets the breakthrough stage for the identification of safer opioid analgesics in primates and sheds light on future clinical interventions with such novel opioid analgesics.
The proposed research is highly relevant to public health because it could result in the identification of a safer opioid analgesic with promising therapeutic profile in primates. Identification of a superior analgesic with fewer side effects has long been a goal of pain management. Such a compound could profoundly impact the practice of opioid analgesia as well as substantially reduce the risks and concerns posed by the currently available mu opioid analgesics.
