AZD-7325 / BAER-101: A Comprehensive Monograph on a Subtype-Selective GABAA Modulator

Executive Summary

AZD-7325 is an investigational small molecule that represents a significant endeavor in the rational design of central nervous system (CNS) therapeutics. Developed initially by AstraZeneca, it is a novel, orally active positive allosteric modulator (PAM) of the γ-aminobutyric acid type A (GABAA) receptor. Its design was predicated on a refined understanding of GABAA receptor neuropharmacology, specifically engineered for high affinity and functional selectivity for receptor subtypes containing α2 and α3 subunits, while demonstrating minimal activity at the α1 and α5 subunits. This profile was hypothesized to confer potent anxiolytic and anticonvulsant effects without the dose-limiting side effects of traditional non-selective benzodiazepines, such as sedation, cognitive impairment, and abuse liability, which are primarily mediated by the α1 and α5 subunits, respectively.

Preclinical studies validated this hypothesis, demonstrating potent anxiolytic-like effects and, more notably, profound anti-seizure activity in robust animal models of epilepsy and Fragile X Syndrome, all with a favorable safety margin. Early-phase clinical trials in healthy volunteers further confirmed its differentiated profile, showing high levels of GABAA receptor occupancy in the brain without inducing the significant CNS impairment characteristic of drugs like lorazepam. Despite this promising profile, AZD-7325 failed to demonstrate statistically significant efficacy over placebo in two large Phase II proof-of-concept trials for Generalized Anxiety Disorder (GAD), its primary target indication. This outcome led AstraZeneca to discontinue its development.