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

这个I-Corps项目更广泛的影响/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（BZD）是最常用的抗焦虑药物，目前超过5%的美国人口使用。 虽然有效，但BZD具有高度成瘾性，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，但BZD仍然被广泛使用，即使是在使用多种药物的高风险人群中。 当BZD与酒精、阿片类药物或其他CNS抑制剂一起服用时，它们可引起危及生命的呼吸抑制以及其他效应，如嗜睡和运动功能降低，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BZD替代品，特别是针对有多种物质过量风险的人。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，提高长期康复成功率，并打击日益流行的多种物质过量死亡。该I-Corps项目基于部分和功能亚型选择性GABAA（γ-氨基丁酸-A）受体调节剂的开发，用于治疗焦虑症，特别是针对物质使用障碍和多种物质过量的高风险个体。选择的天然和合成类黄酮已被证明是有效的GABAAR调节剂，具有抗焦虑活性和降低的镇静和酒精增强作用。然而，黄酮类化合物由于缺乏药物性质而吸收不良并迅速排出。这使我们设计了具有改善的类药物性质的新型衍生物，目的是鉴定不具有酒精和阿片增强性质的类药物抗焦虑剂（GABAAR PAM）。该项目的基础是基于2021年完成的工作，目标是积极调节和抑制乙醇诱导的GABAAR增强作用，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NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.