Literature DB >> 25799373

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

Gabriel Martinez Botella1, Francesco G Salituro1, Boyd L Harrison1, Richard T Beresis2, Zhu Bai3, Kaisheng Shen2, Gabriel M Belfort1, Carlos M Loya1, Michael A Ackley1, Scott J Grossman1, Ethan Hoffmann1, Shiling Jia2, Jiamiao Wang2, James J Doherty1, Albert J Robichaud1.   

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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Year:  2015        PMID： 25799373     DOI： 10.1021/acs.jmedchem.5b00032

Source DB:  PubMed          Journal:  J Med Chem        ISSN： 0022-2623            Impact factor:   7.446


  8 in total

1.  Metabotropic, but not allosteric, effects of neurosteroids on GABAergic inhibition depend on the phosphorylation of GABAA receptors.

Authors:  Manasa L Parakala; Yihui Zhang; Amit Modgil; Jayashree Chadchankar; Thuy N Vien; Michael A Ackley; James J Doherty; Paul A Davies; Stephen J Moss
Journal:  J Biol Chem       Date:  2019-06-25       Impact factor: 5.157

2.  Endogenous and synthetic neuroactive steroids evoke sustained increases in the efficacy of GABAergic inhibition via a protein kinase C-dependent mechanism.

Authors:  Amit Modgil; Manasa L Parakala; Michael A Ackley; James J Doherty; Stephen J Moss; Paul A Davies
Journal:  Neuropharmacology       Date:  2016-10-12       Impact factor: 5.250

3.  Intranasal Allopregnanolone Confers Rapid Seizure Protection: Evidence for Direct Nose-to-Brain Delivery.

Authors:  Dorota Zolkowska; Chun-Yi Wu; Michael A Rogawski
Journal:  Neurotherapeutics       Date:  2021-01-06       Impact factor: 7.620

4.  The synthetic neuroactive steroid SGE-516 reduces seizure burden and improves survival in a Dravet syndrome mouse model.

Authors:  Nicole A Hawkins; Michael Lewis; Rebecca S Hammond; James J Doherty; Jennifer A Kearney
Journal:  Sci Rep       Date:  2017-11-10       Impact factor: 4.379

5.  Enaminone Modulators of Extrasynaptic α4β3δ γ-Aminobutyric AcidA Receptors Reverse Electrographic Status Epilepticus in the Rat After Acute Organophosphorus Poisoning.

Authors:  Timothy B C Johnstone; Hilary S McCarren; Jay Spampanato; F Edward Dudek; John H McDonough; Derk Hogenkamp; Kelvin W Gee
Journal:  Front Pharmacol       Date:  2019-05-24       Impact factor: 5.810

6.  Preventing Phosphorylation of the GABA A R β3 Subunit Compromises the Behavioral Effects of Neuroactive Steroids.

Authors:  Thuy N Vien; Michael A Ackley; James J Doherty; Stephen J Moss; Paul A Davies
Journal:  Front Mol Neurosci       Date:  2022-03-31       Impact factor: 6.261

7.  Inhibition of human macrophage activation via pregnane neurosteroid interactions with toll-like receptors: Sex differences and structural requirements.

Authors:  Irina Balan; Laure Aurelian; Kimberly S Williams; Brian Campbell; Rick B Meeker; A Leslie Morrow
Journal:  Front Immunol       Date:  2022-07-29       Impact factor: 8.786

8.  Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator.

Authors:  Alison L Althaus; Michael A Ackley; Gabriel M Belfort; Steven M Gee; Jing Dai; David P Nguyen; Tatiana M Kazdoba; Amit Modgil; Paul A Davies; Stephen J Moss; Francesco G Salituro; Ethan Hoffmann; Rebecca S Hammond; Albert J Robichaud; Michael C Quirk; James J Doherty
Journal:  Neuropharmacology       Date:  2020-09-22       Impact factor: 5.250
  8 in total

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