Synthesis and evaluation of neuroactive steroids with novel pharmacophore at C-21 let identify a compound with advantageous PK profile and higher EC50 and Emax as PAM on GABAA receptor.

Zuranolone (SAGE-217) is a neuroactive steroid (γ-aminobutyric acid)A (GABAA) receptor positive allosteric modulator (PAM) as the first oral drug approved by the FDA in 2023, which is used to treat patients with postpartum depression (PPD). SAGE-217 has a "black box" warning with impairing ability to drive or engage in other potentially hazardous activities. In addition, SAGE-217 can cause CNS depressant effects such as somnolence and confusion, suicidal thoughts and behavior and embryo-fetal toxicity. Based on the structure-activity relationship (SAR) of SAGE-217, a total of 28 neuroactive steroids with novel pharmacophore at C-21 modulated SAGE-217 derivatives were designed and synthesized. The biological activities were evaluated by both synaptic α1β2γ2 GABAA receptor and extrasynaptic α4β3δ GABAA receptor cell assays. The optimal compound S28 exhibited much more potent potency and similar efficacy at extrasynaptic GABAA receptor than SAGE-217. Different from above, compound S28 exhibited similar potency and lower efficacy at synaptic GABAA receptor than SAGE-217, which were consistent with the analysis of molecular docking and dynamics simulation results. The appropriate lower efficacy at synaptic GABAA receptor of compound S28 might contribute to reduce the side effects of excessive sedation. Furthermore, compound S28 was demonstrated to have excellent in vivo pharmacokinetic (PK) parameters, robust in vivo pharmacodynamic (PD) effects and good safety profiles. Therefore, compound S28 represents a potentially promising treatment of PPD candidate that warrants further investigation.