Development of compound RUEC2-118, a novel partial GABAAR positive modulator, a fast-acting treatment for general anxiety and panic disorder, to prevent opioid and benzodiazepine overdose fatalities.

阿片类药物使用障碍(OUD)在诊断为焦虑症的患者中非常普遍， 超过60%的OUD患者报告患有终生焦虑症。共同发生的焦虑与较早的 进展更快，治疗结果更差，联合使用其他药物的可能性更高 物质，特别是苯二氮卓类(BZD)。BZD目前是FAST的标准护理治疗- 缓解焦虑症和恐慌症。尽管BZD在短期内非常有效，但它代表着 阿片类药物过量流行的主要因素，但往往被忽视。据估计，BZD参与了 在美国，每年有1.2万人死于过量服药，主要原因是与其他中枢神经系统镇静剂同时使用。 事实上，超过90%的苯二氮卓类药物过量死亡涉及阿片类药物，高达30%的阿片类药物 过量涉及BZD，阿片类药物超标率与每个州的BZD处方率直接相关。使用 由于缺乏能够提供类似疗效的更安全的替代品，BZD的市场预测表明，它们的使用将 保持稳定或在全球范围内增加。11因此，迫切需要发展安全和相对有效的 BZD的替代品，适用于患有OUD的人。之前为提高GABAAR PAM安全性而进行的药物发现工作 重点是消除镇静和上瘾的特性，这在临床试验中被证明是很难翻译的， 药物发现的努力也在减弱。然而，有大量证据表明，合成的黄酮类化合物 部分GABAAR PAM可以提供快速有效的抗焦虑活性，其安全性优于BZD和 咪唑苯并二氮(IBZD)衍生物。这启发了我们设计有前途的合成和合成的衍生品 天然伽巴活性黄酮类化合物RU-EC2-118是一种具有EC50的部分伽巴活性PAM α1β3γ2和α2β3γ2 GABAAR亚型的136NM和126NM。虽然有必要进行进一步调查，但我们的 在大鼠模型中进行的体内研究的初步结果有力地支持了RUEC2-118机制的可能性 与其他中枢神经系统抑制药联合使用，可提供有效、快速的抗焦虑活性和更安全的配置文件 物质。具体目标1包括对小鼠的抗焦虑效果研究，通过高架加迷宫和 RUEC2-118(5，10，15 mg/kg PO)和阿普唑仑(0.5 mg/kg PO)。具体目标2包括呼吸抑制 RUEC2-118(15 mg/kg ip)、阿普唑仑(0.5 mg/kg ip)与芬太尼同时给药对小鼠的影响 (0.25 mg/kg)。具体目标1和2旨在测试该机制的可行性 RUEC2-118在不增强阿片类药物诱导的呼吸的情况下提供有效的速效抗焦虑活性 抑郁症。具体目标3旨在测试我们创新的可取性，并包括注册 NIH I-Corps计划和与FDA的IND前会议安排。成功地翻译了我们的 这项研究将为开发一种安全有效的抗焦虑药物奠定基础，这种药物可以 防止未来阿片类药物和苯二氮卓类药物过量死亡。

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.