PROJECT SUMMARY Opioid use in the United States has been at epidemic proportions for many years. Concerted efforts across the spectrum of political, social awareness, clinical and research initiatives have so far been unable to curb the rising rates of opioid use and opioid overdose deaths across the USA. From the treatment standpoint, a number of novel therapies to alleviate the severe opioid withdrawal symptoms and/or reduce risk of relapse continue to be proposed. A significant portion of research into potential therapies focuses on testing FDA-approved drugs as potential treatments for opioid use. Such approach relies on the verified scientific rationale and clinically validated 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 an adjunct to existing opioid use therapies. Therapeutics effects of memantine are due to the involvement of glutamatergic pathways in the development and maintenance of opioid addiction, and its clinical tolerability likely derives from preferential inhibition of NMDA receptors located outside the synapse, since broad spectrum NMDA receptor antagonists are associated with serious clinical side effects. However, memantine concentrations must be kept low to take advantage of its preferential antagonism, because at higher (and more therapeutically relevant) concentrations, memantine may inhibit synaptic NMDA receptors and trigger side effects. To resolve this problem, NeurANO Bioscience created a nanoparticle-based (AuM) conjugate comprising several memantine molecules. Due to its dimensions, AuM cannot access the synaptic cleft and synaptic NMDA receptors, but allows activation of extrasynaptic NMDAR receptors with the potency greatly exceeding that of free memantine. During Phase I studies, we discovered that AuM can drastically minimize the opioid withdrawal symptoms, and demonstrated that AuM can be delivered into the brain at therapeutic concentrations using intranasal administration. During proposed Phase II studies, we will proceed with efforts directed at establishing the commercial manufacturability of AuM, determining optimal administration routes and AuM dosage for the treatment of opioid withdrawal symptoms, and exploring AuM therapeutic potential for the prevention of acquisition of opioid dependence and/or relapse. Using the data acquired during Phase II studies, we will develop the efficient strategy to pursue IND-enabling studies for use of exclusive antagonists of extrasynaptic NMDARs in the treatment of OUD.

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.