Opioid use disorder (OUD) is highly prevalent among individuals with diagnosed anxiety disorders with more than 60% of individuals with OUD reporting a lifetime anxiety disorder. Co-occurring anxiety is linked to earlier and more rapid progression into OUD, poorer treatment outcomes, and high probability of co-use of other substances, particularly benzodiazepines (BZDs). BZDs are currently the standard of care treatment for fast- acting relief for general anxiety and panic disorder. Although highly effective in the short-term, BZDs represent a major, but often overlooked contributor to the opioid overdose epidemic. BZDs are involved in an estimated 12,000 overdose fatalities each year in the US, largely due to the concomitant use with other CNS depressants, such as opioids3 In fact, more than 90% of benzodiazepine overdose fatalities involve opioids, up to 30% opioid overdoses involve BZDs, and opioid overdose rates are directly linked to BZD prescribing rates per state. With a lack of safer alternatives that can offer comparable efficacy, BZD market predictions indicate their use will remain steady or increase globally.11 Thus, there is an urgent need to develop safe and comparably effective alternatives to BZDs for those with OUD. Previous drug discovery efforts to improve safety of GABAAR PAMs focused on elimination of sedative and addictive properties, which proved difficult to translate in clinical trials, and drug discovery efforts have waned. However, there is substantial evidence that synthetic flavone derived partial GABAAR PAMs can provide fast-acting anxiolytic activity with improved safety profiles over BZD and imidazobenzodiazepine (iBZD) derivatives. This inspired us to design derivatives of promising synthetic and natural GABAAR active flavones, leading to the discovery of RU-EC2-118, a partial GABAAR PAM with an EC50 of 136 nM and 126 nM at α1β3γ2 and α2β3γ2 GABAAR subtypes. While further investigation is necessary, our preliminary results, in vivo studies in rat models, strongly support the potential for the mechanism of RUEC2-118 to provide effective fast-acting anxiolytic activity and a safer profile with co-use with other CNS-depressing substances. Specific Aim 1 includes anxiolytic efficacy studies in mice, as measured by elevated plus maze with RUEC2-118 (5,10, 15 mg/kg PO) and alprazolam (0.5 mg/kg PO). Specific Aim 2 includes respiratory depression studies in mice with RUEC2-118 (15 mg/kg IP), alprazolam (0.5 mg/kg IP) with and without concurrent fentanyl (0.25 mg/kg) administration. Specific Aims 1 and 2 are intended to test the feasibility of the mechanism of RUEC2-118 to provide effective fast-acting anxiolytic activity without enhancing opioid-induced respiratory depression. Specific Aim 3 is intended to test the desirability of our innovation and includes enrollment in the NIH I-Corps program and scheduling of a pre-IND meeting with the FDA. The successful translation of our research will groundwork for the development of a safe and effective anxiolytic for individuals with OUD that can prevent future opioid and benzodiazepine overdose fatalities.

Project Narrative Unlike benzodiazepines (full GABAAR PAMs), which are the current standard for fast-acting treatment of general anxiety and panic disorder and are involved in more than 12,000 overdose fatalities each year in the US alone, our novel partial GABAAR PAM will help prescribers who want to ensure the safety of prescribed medications in individuals with history of OUD, who are at high risk for misuse. Even if co-used with opioids, our compound is hypothesized to reduce the overdose risks and to prevent polysubstance overdose fatalities.