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2015•Journal of Medicinal ChemistryRequires access

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

Gabriel Martinez Botella, Francesco G. Salituro, Boyd L. Harrison, Richard T. Beresis, Zhu Bai, Kaisheng Shen, Gabriel M. Belfort, Carlos M. Loya, Michael A. Ackley, Scott J. Grossman, Ethan C. Hoffmann, Shiling Jia, Jiamiao Wang, James Doherty, Albert J. Robichaud

Open publisher page 56 citations

Abstract

Neuroactive steroids (NASs) have been shown to impact central nervous system (CNS) function through positive allosteric modulation of the GABA(A) receptor (GABA(A)-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 GABA(A) receptor modulator, and SGE-872, a selective extrasynaptic GABA(A) receptor modulator. Both molecules possess excellent druglike properties, making them advanced leads for oral delivery of GABA(A) receptor modulators.

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What this paper is about

Neuroactive steroids (NASs) have been shown to impact central nervous system (CNS) function through positive allosteric modulation of the GABA(A) receptor (GABA(A)-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 GABA(A) receptor modulator, and SGE-872, a selective extrasynaptic GABA(A) receptor modulator. Both molecules possess excellent druglike properties, making them advanced leads for oral delivery of GABA(A) receptor modulators.

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OpenAlex reports 56 citations for this work. Citation counts describe recorded attention and do not establish research quality.

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Available abstract

Neuroactive steroids (NASs) have been shown to impact central nervous system (CNS) function through positive allosteric modulation of the GABA(A) receptor (GABA(A)-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 GABA(A) receptor modulator, and SGE-872, a selective extrasynaptic GABA(A) receptor modulator. Both molecules possess excellent druglike properties, making them advanced leads for oral delivery of GABA(A) receptor modulators.

Key concepts: Allosteric regulation, Chemistry, Neuroactive steroid, Allosteric modulator, Pregnanolone, Receptor, GABAA receptor, Pharmacology

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