# Synthesis and Evaluation of a Novel Zuranolone Analog with High GABAA Receptor PAM Activity and Excellent Pharmacokinetic Profiles

## TL;DR

Researchers developed a new Zuranolone analog with improved brain activity and longer effects, making it a better treatment for depression and epilepsy.

## Contribution

A novel C-21 modified Zuranolone analog with enhanced GABAA receptor activity and pharmacokinetics was synthesized and evaluated.

## Key findings

- S9 showed 2.5-fold greater potency and efficacy than Zuranolone at GABAA receptors.
- S9 had 5-fold longer plasma half-life and 6-fold higher AUC in rats.
- S9 outperformed Zuranolone in seizure suppression and LORR threshold in rats.

## Abstract

Zuranolone (SAGE-217), the first FDA-approved oral neurosteroid (NAS), a positive allosteric modulator (PAM) of γ-aminobutyric acid type A (GABAA) receptor for postpartum depression approved in 2023, has limitations such as short half-life, low bioavailability, and central inhibitory side effects. To address these, we designed novel C-21 modified derivatives of Zuranolone, identifying the triazolone scaffold as key for enhancing GABAA activity. Here, we synthesized Zuranolone analogs with diverse triazolone substituents, finding that pyridine-derived modifications improved the activity correlated with LogP. The optimal derivative, S9 (2-(trifluoroethoxy)pyridine-triazolone, LogP 4.61), showed 2.5-fold greater potency (EC50) and efficacy (Emax) than Zuranolone (LogP 4.78) at synaptic/extrasynaptic GABAA receptors, attributed to stronger binding via molecular docking. In rats, S9 exhibited 5-fold longer plasma T1/2, 6-fold higher AUC, 3-fold greater brain exposure, and 30% improved bioavailability. It also outperformed Zuranolone in pentylenetetrazole (PTZ)-induced seizure suppression and threshold dose for loss of righting reflex (LORR) in rats. The C21-pyridine-triazolone pharmacophore in S9 enhances receptor activity potency without increasing lipophilicity, optimizing pharmacokinetics and safety, which makes it a promising therapeutic candidate for depression and epilepsy.