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 for opioid use disorder (OUD) to manage patients abusing
heroin, fentanyl, oxycodone and related drugs. 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 naloxone 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 the negative
side-effects of current agonist or antagonist treatments. Our hypothesis is that NAMs of MOR (mu-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 mu-NAMs as an alternative, non-agonist treatment for OUD. In a previous
U18 “Step up for Substance Abuse” grant (DA DA052371) we identified a lead mu-NAM that is active in vitro,
shows good brain penetration after intraperitoneal injection, and is effective in vivo in blocking MOR-mediated
agonist actions in the mouse. However, this compound is not patentable (i.e., it is not a new chemical entity)
and lacks drug-like characteristics. The objective of the current application is to develop our original lead
molecule to obtain a mu-NAM that has high affinity for the allosteric site on MOR, is selective for MOR, has
appropriate solubility and pharmacokinetic properties, is functional in vivo, and around which we can develop
intellectual property. Towards this aim in this Phase 1 application, we will 1) Synthesize and evaluate in vitro
derivations of our initial mu-NAM lead to identify structurally novel mu-NAMs, and 2) De-risk the project by
confirming our lead mu-NAM has activity in both the mouse and the rat and in both males and females.Project Narrative
Opioid Abuse Disorder (OUD) is a serious problem in the United States and throughout the world, with
increasing harm and burden to the individual, their families and society. Therefore, there is a major unmet need
for more efficient and effective methods to help patients suffering from OUD. In this project we will develop a
series of medications that target the opioid receptor in a novel fashion to manage OUD, while avoiding the
unwanted effects of currently available treatment medications.