Development of negative allosteric modulators of the mu-opioid receptor for the management of opioid use disorder

Abstract There is a significant need for new treatments to manage the multitude of patients suffering from opioid use disorder (OUD). Buprenorphine and methadone are both effective medications for OUD but are agonists with potential for abuse and diversion, and with methadone the risk of respiratory depression and overdose death. Moreover, these compounds are not effective in relapse situations. The antagonist naltrexone is an alternative that does prevent relapse but has poor patient compliance due to its complete blockade of the mu-opioid system. We have discovered compounds that act as non-competitive antagonists of the mu-opioid receptor (MOR). These compounds interact with a novel site on the receptor to function as allosteric antagonists, also called NAMs or Negative Allosteric Modulators. They reduce the activity of MOR agonists in a fashion that is non-surmountable and that does not completely shut down the receptor, thereby providing the ability to reduce opioid actions in individuals with OUD, potentially without inducing withdrawal and lacking the negative side-effects of current agonist or antagonist treatments. Our hypothesis is that NAMs of MOR (MOR-NAMs) could be developed as effective non- agonist treatments for OUD by targeting MOR in a novel way leading to our goal of identifying proprietary MOR-NAMs as an improved, non-agonist treatment for OUD. In Phase 1 of this STTR application (R41, DA056254) we identified several proprietary MOR-NAM’s with high potency at MOR, that are active in vitro, block actions of morphine in mice and are orally bioavailable. The objective of the Phase 2 application is to develop these NAM molecules into druggable compounds with favorable DMPK characteristics, no obvious toxicity or off-target liabilities, a complete lack of any MOR agonist activity and that inhibit fentanyl seeking behavior in rat self-administration models. At the end of this Phase 2 work, we expect to be in a very favorable position to seek strategic partnerships to fund large-scale chemical synthesis and in vivo toxicology as we towards an IND application and eventual clinical trials.