Neuroactive Steroids. 1. Positive Allosteric Modulators of the (γ-Aminobutyric Acid)A Receptor: Structure–Activity Relationships of Heterocyclic Substitution at C-21

Neuroactive steroids (NASs) have been shown to impact central nervous system (CNS) function through positive allosteric modulation of the GABAA receptor (GABAA-R). Herein we report the effects on the activity and pharmacokinetic properties of a series of nor-19 pregnanolone analogues bearing a heterocyclic substituent at C-21. These efforts resulted in the identification of SGE-516, a balanced synaptic/extrasynaptic GABAA receptor modulator, and SGE-872, a selective extrasynaptic GABAA receptor modulator. Both molecules possess excellent druglike properties, making them advanced leads for oral delivery of GABAA receptor modulators.