I-Corps: Flavonoid derivative for treatment of anxiety without alcohol or opiate enhancing properties

I-Corps项目的更广泛影响/商业潜力是开发安全有效的焦虑治疗方法，特别是针对物质使用障碍和多种物质过量的高风险个体。苯二氮卓类药物（BZDs）是最常用的抗焦虑药物，目前有超过5%的美国人服用。虽然有效，bzd是高度成瘾性的，通常涉及多种物质过量死亡。事实上，每个州的BZD处方率与过量死亡率直接相关。尽管存在这种风险，bzd仍然被广泛使用，即使在那些使用多种物质的高风险人群中也是如此。当bzd与酒精、阿片类药物或其他中枢神经系统抑制剂一起服用时，它们会导致危及生命的呼吸抑制，以及其他影响，如嗜睡和运动功能下降，这通常会导致事故和住院治疗。拟议的研究致力于开发更安全有效的BZDs替代品，特别是那些有多物质过量风险的人。在这样做的过程中，目标是提高焦虑治疗和物质使用障碍的安全性和有效性，提高长期康复的成功率，并打击日益流行的多种物质过量死亡。I-Corps项目的基础是开发部分和功能性亚型选择性GABAA （γ -氨基丁酸- a）受体调节剂，用于治疗焦虑，特别是针对有物质使用障碍和多物质过量高风险的个体。精选的天然和合成类黄酮已被证明是有效的GABAAR调节剂，具有抗焦虑活性，减少镇静和酒精增强作用。然而，由于缺乏类似药物的特性，类黄酮吸收不良，排泄迅速。这使我们设计了具有改进的类似药物性质的新型衍生物，目的是确定一种类似药物的抗焦虑（GABAAR PAM），而不具有酒精和鸦片增强性质。该项目的基础是基于2021年完成的工作，目标是正调节和抑制乙醇诱导的GABAARs增强，作为治疗酒精使用障碍的新机制。这项工作还导致了一项临时专利的申请，并在最近发表。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this I-Corps project is the development of safe and effective treatments for anxiety, specifically for individuals at high risk of substance use disorders and polysubstance overdoses. Benzodiazepines (BZDs) are the most commonly prescribed class of anti-anxiety medication, and currently prescribed to more than 5% of the US population. Although effective, BZDs are highly addictive and commonly involved in polysubstance overdose fatalities. In fact, BZD prescription rates per state are directly linked to overdose fatality rates. Despite this risk, BZDs remain widely prescribed, even in those at high risk for polysubstance use. When BZDs are taken with alcohol, opiates, or other CNS depressants, they can cause life threatening respiratory depression among other effects such as drowsiness and reduced motor function, which often lead to accidents and hospitalizations. The proposed research is committed to the development safer and effective alternatives to BZDs, specifically for those at risk of polysubstance overdose. In doing so, the goal to improve safety and efficacy of anxiety treatment and substance use disorders, improve long-term recovery success, and combat the rising pandemic of polysubstance overdose fatalities. This I-Corps project is based on the development of partial and functionally subtype selective GABAA (Gamma-Amino Butyric Acid-A) receptor modulators for the treatment of anxiety, specifically for individuals at high risk of substance use disorders and polysubstance overdoses. Select natural and synthetic flavonoids have been shown to be potent GABAAR modulators with anxiolytic activity and reduced sedative and alcohol-enhancing effects. However, flavonoids are poorly absorbed and rapidly excreted due to a lack of druglike properties. This has led us to the design of novel derivatives with improved druglike properties with the aim of identifying a druglike anti-anxiety (GABAAR PAM) without alcohol and opiate enhancing properties. The foundation for this project is based upon work completed in 2021 targeting positive modulation and inhibition ethanol-induced potentiation of GABAARs as a novel mechanism for the treatment of alcohol use disorder. This work also led to the filing of a provisional patent, and a recent publication.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.