Biasing Mu Opioid Receptor Signaling in vivo

Summary Prescription opioid narcotics, such as morphine, oxycodone, and fentanyl, produce analgesia and side effects through activation of the mu opioid receptor (MOR), a G protein coupled receptor (GPCR). Our long- standing goal is to understand how MOR signals to produce distinct biological effects and to ultimately influence the development of therapeutics that will take advantage of “good” receptor signaling (pain relief) and avoid “bad” receptor signaling that leads to unwanted opioid side effects like respiratory suppression and tolerance. It has become increasingly evident that different drug structures can elicit different receptor signaling cascades at a single receptor, likely by changing the affinities for association with intracellular binding partners. Over the past decade, we have developed a series of agonists that act in a manner that drives G protein signaling downstream of MOR and induce little interactions between the receptor and arrestin2, a scaffolding protein. Moreover, we have determined that several of these agonists produce antinociception without inducing respiratory suppression. One compound, SR-17108 has been shown to be potent and efficacious in a neuropathic pain model where it performed better than oxycodone or morphine. Chronic treatment with SR-17018 did not lead to tolerance in the mouse models. Extensive biochemical studies have recently revealed that at least 4 agonists from this class, including SR-17018, are binding to different sites on the receptor and are therefore noncompetitive or allosteric agonists. In this proposal, we want to determine if it is this noncompetitive property, or other pharmacological properties that the compounds possess that confer the favorable physiological profiles. Further, we are seeking to determine the binding site of these compounds. Since the compounds bind to different sites on the receptor than conventional opioid drugs, we will ask how the allosteric compounds interact with morphine, fentanyl and naloxone when administered together.