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）在诊断为焦虑症的个体中非常普遍， 超过60%的OUD患者报告终生患有焦虑症。共同发生的焦虑与早期 更快进展为OUD，治疗结局较差，与其他药物联合使用的可能性较高。 药物，特别是苯二氮卓类（BZD）。BZD目前是快速- 缓解一般性焦虑和恐慌症。虽然在短期内非常有效，但BZD代表 一个主要的，但往往被忽视的贡献者阿片类药物过量流行病。BZD参与了估计 美国每年有12，000例过量死亡，主要是由于与其他CNS抑制剂合并使用， 事实上，超过90%苯二氮卓类药物过量致死涉及阿片类药物，高达30%阿片类药物 过量涉及BZD，阿片类药物过量率与每个州的BZD处方率直接相关。与 缺乏更安全的替代品，可以提供可比的功效，BZD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，迫切需要开发安全有效的 BZD的替代品。以前的药物发现努力，以提高安全性的GABAAR PAM 专注于消除镇静和成瘾特性，这在临床试验中证明很难转化， 药物发现的努力已经减弱。然而，有大量证据表明，合成黄酮衍生 部分GABAAR PAM可提供速效抗焦虑活性，安全性优于BZD， 咪唑并苯并二氮杂（iBZD）衍生物。这启发了我们设计有前途的合成和 天然GABAAR活性黄酮，导致发现RU-EC 2 -118，一种EC 50 在α1β3γ2和α2β3γ2 GABAAR亚型中分别为136 nM和126 nM。虽然需要进一步调查，但我们 初步结果，在大鼠模型中的体内研究，强烈支持RUEC 2 -118的机制的潜力 提供有效的速效抗焦虑活性和与其他CNS抑制剂共同使用的更安全的特征， 物质.具体目标1包括小鼠中的抗焦虑功效研究，如通过高架十字迷宫测量的， RUEC 2 -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 在小鼠中进行的RUEC 2 -118（15 mg/kg IP）、阿普唑仑（0.5 mg/kg IP）联合和不联合芬太尼的研究 (0.25 mg/kg）给药。具体目标1和2旨在测试以下机制的可行性： RUEC 2 -118提供有效的速效抗焦虑活性，而不增强阿片样物质诱导的呼吸抑制。 萧条具体目标3旨在测试我们的创新的可取性，并包括在 NIH I-Corps计划和与FDA的IND前会议安排。我们的成功翻译 这项研究将为开发一种安全有效的抗焦虑药奠定基础， 防止未来阿片类药物和苯二氮卓类药物过量致死。

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.