Opioid use in the United States has been at epidemic proportions for many years. Concerted efforts acrossthe spectrum of political, social awareness, clinical and research initiatives have so far been unable to curb therising rates of opioid use and opioid overdose deaths across the USA. From the treatment standpoint, a numberof novel therapies to alleviate the severe opioid withdrawal symptoms and/or reduce risk of relapse continue tobe proposed. A significant portion of research into potential therapies focuses on testing FDA-approved drugsas potential treatments for opioid use. Such approach relies on the verified scientific rationale and clinicallyvalidated drug targets to ensure that these studies will produce efficacious new drugs for opioid use disorder. One of such drugs is memantine, an NMDA receptor antagonist, that has shown encouraging results as anadjunct to existing opioid use therapies. Therapeutics effects of memantine are due to the involvement ofglutamatergic pathways in the development and maintenance of opioid addiction, and its clinical tolerability likelyderives from preferential inhibition of NMDA receptors located outside the synapse, since broad spectrum NMDAreceptor antagonists are associated with serious clinical side effects. However, memantine concentrations mustbe kept low to take advantage of its preferential antagonism, because at higher (and more therapeuticallyrelevant) concentrations, memantine may inhibit synaptic NMDA receptors and trigger side effects. To resolve this problem, NeurANO Bioscience created a nanoparticle-based (AuM) conjugate comprisingseveral memantine molecules. Due to its dimensions, AuM cannot access the synaptic cleft and synaptic NMDAreceptors, but allows activation of extrasynaptic NMDAR receptors with the potency greatly exceeding that offree memantine. During Phase I studies, we discovered that AuM can drastically minimize the opioid withdrawalsymptoms, and demonstrated that AuM can be delivered into the brain at therapeutic concentrations usingintranasal administration. During proposed Phase II studies, we will proceed with efforts directed at establishingthe commercial manufacturability of AuM, determining optimal administration routes and AuM dosage for thetreatment of opioid withdrawal symptoms, and exploring AuM therapeutic potential for the prevention ofacquisition of opioid dependence and/or relapse. Using the data acquired during Phase II studies, we willdevelop the efficient strategy to pursue IND-enabling studies for use of exclusive antagonists of extrasynapticNMDARs in the treatment of OUD.
Public Health Relevance Statement: PROJECT NARRATIVE
Despite concerted efforts to address the opioid epidemic in the United States, the opioid overdose death rates
are still high, and the opioid use is still on the rise. This unfortunate reality demands the development of novel
therapeutic approaches, preferably with non-opioid mechanisms of action. NMDAR-mediated pathways are
implicated in several processes underlying the development and maintenance of addiction, and therefore
NMDAR antagonists may be able to prevent the formation of compulsive drug-taking behaviors, reduce physical
opioid withdrawal symptoms, and/or prevent relapse. In an effort to contribute to the fight against OUD, we
developed a novel NMDAR-targeting nanotherapeutic that is expected to exhibit enhanced therapeutic efficacy
and improved safety profile because it can only block NMDARs outside the synapses. In the proposed project,
we will evaluate the safety and abuse potential of our nanotherapeutic, and explore the entire spectrum of its
potential therapeutic effects in animal models of opioid addiction.
Project Terms: 