SBIR-STTR Award

There is a significant need for new treatments for opioid use disorder (OUD) to manage patients abusingheroin, fentanyl, oxycodone and related drugs. Buprenorphine and methadone are both effective medicationsfor OUD but are agonists with potential for abuse and diversion, and with methadone the risk of respiratorydepression and overdose death. Moreover, these compounds are not effective in relapse situations. Theantagonist naloxone is an alternative that does prevent relapse but has poor patient compliance due to itscomplete blockade of the mu-opioid system. We have discovered compounds that act as non-competitiveantagonists of the mu-opioid receptor (MOR). These compounds interact with a novel site on the receptor tofunction as allosteric antagonists, also called NAMs or Negative Allosteric Modulators. They reduce the activityof 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 negativeside-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 toour goal of identifying proprietary mu-NAMs as an alternative, non-agonist treatment for OUD. In a previousU18 "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-mediatedagonist 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 leadmolecule to obtain a mu-NAM that has high affinity for the allosteric site on MOR, is selective for MOR, hasappropriate solubility and pharmacokinetic properties, is functional in vivo, and around which we can developintellectual property. Towards this aim in this Phase 1 application, we will 1) Synthesize and evaluate in vitroderivations of our initial mu-NAM lead to identify structurally novel mu-NAMs, and 2) De-risk the project byconfirming our lead mu-NAM has activity in both the mouse and the rat and in both males and females.

Public Health Relevance Statement:
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.

Project Terms:
<3, 5 cyclic AMP synthetase><μ opioid receptors><μ-OR><μOR><β-arrestin>