Effects of a G protein-biased mu opioid receptor agonist PZM21 in primates

Wake Forest University Health Sciences, Winston-Salem NC

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Abstract

Mu opioid peptide (MOP) receptor agonists such as morphine are the most widely used analgesics for pain management. However, MOP receptor agonist-assoicated abuse liability 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 retain analgesic effects, but they are devoid of MOP receptor-mediated side effects. Such compounds have not been studied systemically in non-human primate (NHP) models with translational potential. In this application, we select a newly discovered G protein-baised MOP receptor agonist, PZM21, which will be synthesized by Dr. Yanan Zhang at Research Triangle Institute. A series of NHP experiments will be conducted to evaluate effects of PZM21 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 (abuse liability, respriatory depression, constipation, physical dependence, and tolerance) of opioid analgesics. The possibility that drugs with G protein-biased agonism will be effective analgesics with reduced side effects encourages our pharmacological studies of PZM21 in NHP models. Our unique set of physiological and behavioral assays in awake, behaving rhesus monkeys, in combination with the availability of a novel G protein-biased MOP receptor agonist PZM21, sets the breakthrough stage for the identification of safe, non-addictive analgesics in primates and sheds light on future clinical interventions with novel opioid analgesics.