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

Rutgers University New Brunswick, New Brunswick NJ

Investigators

Abstract

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.