3β-Methyl-Neurosteroid Analogs Are Preferential Positive Allosteric Modulators and Direct Activators of Extrasynaptic δ-Subunit γ-Aminobutyric Acid Type A Receptors in the Hippocampus Dentate Gyrus Subfield

No abstract is available for this paper.

• Publication year

  2018

• Venue

  Journal of Pharmacology and Experimental Therapeutics

• Publication date

  2018-06-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1124/jpet.117.246660PMID 29602830PMCID PMC5941194
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Genetic and Molecular Regulation of Extrasynaptic GABA-A Receptors in the Brain: Therapeutic Insights for Epilepsy

  2018influential reference
• GABA-A Receptors Mediate Tonic Inhibition and Neurosteroid Sensitivity in the Brain.

  2018influential reference
• Role of β2/3-specific GABA-A receptor isoforms in the development of hippocampus kindling epileptogenesis.

  2018cited by this paper
• A resurging boom in new drugs for epilepsy and brain disorders

  2018cited by this paper
• PR-independent neurosteroid regulation of α2-GABA-A receptors in the hippocampus subfields.

  2017cited by this paper
• Randomized, double‐blind, placebo‐controlled phase 2 study of ganaxolone as add‐on therapy in adults with uncontrolled partial‐onset seizures

  2017cited by this paper
• Catamenial‐like seizure exacerbation in mice with targeted ablation of extrasynaptic δGABA‐a receptors in the brain

  2017cited by this paper
• Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy.

  2017cited by this paper
• Endogenous and synthetic neuroactive steroids evoke sustained increases in the efficacy of GABAergic inhibition via a protein kinase C‐dependent mechanism

  2017cited by this paper
• Neurosteroid Structure-Activity Relationships for Functional Activation of Extrasynaptic δGABAA Receptors

  2016influential reference
• Neurosteroids for the potential protection of humans against organophosphate toxicity

  2016influential reference
• Zinc Selectively Blocks Neurosteroid-Sensitive Extrasynaptic δGABAA Receptors in the Hippocampus

  2016cited by this paper
• Catamenial Epilepsy: Discovery of an Extrasynaptic Molecular Mechanism for Targeted Therapy

  2016influential reference
• Clinical Potential of Neurosteroids for CNS Disorders.

  2016cited by this paper
• Progress report on new antiepileptic drugs: A summary of the Twelfth Eilat Conference (EILAT XII).

  2015cited by this paper
• Antiseizure Activity of Midazolam in Mice Lacking δ-Subunit Extrasynaptic GABAA Receptors

  2015cited by this paper
• Altered expression of δGABAA receptors in health and disease.

  2015cited by this paper
• Modulation of neurosteroid potentiation by protein kinases at synaptic- and extrasynaptic-type GABAA receptors

  2015cited by this paper
• The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome

  2015cited by this paper
• Neurosteroid analogues. 18. Structure-activity studies of ent-steroid potentiators of γ-aminobutyric acid type A receptors and comparison of their activities with those of alphaxalone and allopregnanolone.

  2014cited by this paper
• Phosphorylation of GABAA receptors influences receptor trafficking and neurosteroid actions

  2014cited by this paper
• Perimenstrual-Like Hormonal Regulation of Extrasynaptic δ-Containing GABAA Receptors Mediating Tonic Inhibition and Neurosteroid Sensitivity

  2014influential reference
• Neurosteroids promote phosphorylation and membrane insertion of extrasynaptic GABAA receptors

  2014cited by this paper
• Estrous Cycle Regulation of Extrasynaptic δ-Containing GABAA Receptor-Mediated Tonic Inhibition and Limbic Epileptogenesis

  2013cited by this paper
• Neurosteroid interactions with synaptic and extrasynaptic GABAA receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability

  2013cited by this paper
• Neuroactive steroids for the treatment of status epilepticus

  2013cited by this paper
• Activity‐dependent phosphorylation of GABAA receptors regulates receptor insertion and tonic current

  2012cited by this paper
• Neurosteroids — Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy -- Jasper's Basic Mechanisms of the Epilepsies

  2012cited by this paper
• A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

  2012cited by this paper
• Profound Desensitization by Ambient GABA Limits Activation of δ-Containing GABAA Receptors during Spillover

  2011cited by this paper
• Ganaxolone

  2011cited by this paper
• Development and Persistence of Limbic Epileptogenesis Are Impaired in Mice Lacking Progesterone Receptors

  2011cited by this paper
• Protein Kinase C Phosphorylation Regulates Membrane Insertion of GABAA Receptor Subtypes That Mediate Tonic Inhibition*

  2010cited by this paper
• Ganaxolone suppression of behavioral and electrographic seizures in the mouse amygdala kindling model.

  2010cited by this paper
• The Testosterone-Derived Neurosteroid Androstanediol Is a Positive Allosteric Modulator of GABAA Receptors

  2010influential reference
• Disease-modifying activity of progesterone in the hippocampus kindling model of epileptogenesis.

  2010cited by this paper
• The influence of neuroactive steroid lipophilicity on GABAA receptor modulation: evidence for a low-affinity interaction.

  2009cited by this paper
• Neurosteroid modulation of GABAA receptors: molecular determinants and significance in health and disease.

  2008cited by this paper
• Neuroactive steroids

  2007cited by this paper
• Neurosteroid binding sites on GABA(A) receptors.

  2007cited by this paper
• Clinical Evaluation of Ganaxolone in Pediatric and Adolescent Patients with Refractory Epilepsy

  2007cited by this paper
• Allopregnanolone Analogs That Positively Modulate GABAA Receptors Protect against Partial Seizures Induced by 6‐Hz Electrical Stimulation in Mice

  2004cited by this paper
• Ganaxolone: A prospective overview

  2004cited by this paper
• Anticonvulsant Activity of Progesterone and Neurosteroids in Progesterone Receptor Knockout Mice

  2004cited by this paper
• Intact synaptic GABAergic inhibition and altered neurosteroid modulation of thalamic relay neurons in mice lacking delta subunit.

  2003cited by this paper
• Phosphorylation influences neurosteroid modulation of synaptic GABAA receptors in rat CA1 and dentate gyrus neurones.

  2003influential reference
• Neurosteroids Shift Partial Agonist Activation of GABAA Receptor Channels from Low- to High-Efficacy Gating Patterns

  2003cited by this paper
• Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABAA receptors

  2003cited by this paper
• Reduced Inhibition and Sensitivity to Neurosteroids in Hippocampus of Mice Lacking the GABAA Receptor δ Subunit

  2003cited by this paper
• Protective efficacy of neuroactive steroids against cocaine kindled-seizures in mice.

  2003cited by this paper
• Reduced inhibition and sensitivity to neurosteroids in hippocampus of mice lacking the GABA(A) receptor delta subunit.

  2003cited by this paper
• Enhanced neurosteroid potentiation of ternary GABA(A) receptors containing the delta subunit.

  2002cited by this paper
• Slow phases of GABAA receptor desensitization: structural determinants and possible relevance for synaptic function

  2002cited by this paper
• Brain Sterols in the AY‐9944 Rat Model of Atypical Absence Seizures

  2002cited by this paper
• Behavior and Physiology of Mice Lacking the GABAA‐Receptor δ Subunit

  2002cited by this paper
• GABA(A) receptor changes in delta subunit-deficient mice: altered expression of alpha4 and gamma2 subunits in the forebrain.

  2002cited by this paper
• Stress-Induced Deoxycorticosterone-Derived Neurosteroids Modulate GABAA Receptor Function and Seizure Susceptibility

  2002cited by this paper
• GABAA receptor changes in δ subunit‐deficient mice: Altered expression of α4 and γ2 subunits in the forebrain

  2002cited by this paper
• GABA(A) receptor delta subunit deletion prevents neurosteroid modulation of inhibitory synaptic currents in cerebellar neurons.

  2002cited by this paper
• Pharmacological characterization of a novel cell line expressing human α4β3δ GABAA receptors

  2002cited by this paper
• Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors.

  2002cited by this paper
• Behavior and physiology of mice lacking the GABAA-receptor delta subunit.

  2002cited by this paper
• Enhanced Anticonvulsant Activity of Neuroactive Steroids in a Rat Model of Catamenial Epilepsy

  2001cited by this paper
• Generating diversity at GABAergic synapses.

  2001influential reference
• Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, add-on trial.

  2000cited by this paper
• Enantioselectivity of pregnanolone-induced gamma-aminobutyric acid(A) receptor modulation and anesthesia.

  2000cited by this paper
• Neurosteroid Modulation of GABA IPSCs Is Phosphorylation Dependent

  2000cited by this paper
• Enantioselectivity of Pregnanolone-Induced γ-Aminobutyric AcidA Receptor Modulation and Anesthesia

  2000cited by this paper
• Acute and chronic effects of the synthetic neuroactive steroid, ganaxolone, against the convulsive and lethal effects of pentylenetetrazol in seizure-kindled mice: comparison with diazepam and valproate.

  2000cited by this paper
• Assessment of Ganaxolone's Anticonvulsant Activity Using a Randomized, Double‐Blind, Presurgical Trial Design

  2000cited by this paper
• Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself.

  2000influential reference
• Effect of Ganaxolone on Flurothyl Seizures in Developing Rats

  2000cited by this paper
• GABAA Receptor Phosphorylation and Functional Modulation in Cortical Neurons by a Protein Kinase C-dependent Pathway*

  2000cited by this paper
• Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice.

  1999influential reference
• Adjacent phosphorylation sites on GABAA receptor beta subunits determine regulation by cAMP-dependent protein kinase.

  1998cited by this paper
• Into orbit

  1998cited by this paper
• Initial Human Experience with Ganaxolone, a Neuroactive Steroid with Antiepileptic Activity

  1997influential reference
• Ligand-Gated Ion Channel Subunit Partnerships: GABAAReceptor α6 Subunit Gene Inactivation Inhibits δ Subunit Expression

  1997cited by this paper
• Effects of PKC activation and receptor desensitization on neurosteroid modulation of GABA(A) receptors.

  1997cited by this paper
• Characterization of the Anticonvulsant Properties of Ganaxolone (CCD 1042; 3α-Hydroxy-3β-methyl-5α-pregnan-20-one), a Selective, High-Affinity, Steroid Modulator of the γ-Aminobutyric AcidA Receptor

  1997influential reference
• 3α-Hydroxy-3β-(phenylethynyl)-5β-pregnan-20-ones: Synthesis and Pharmacological Activity of Neuroactive Steroids with High Affinity for GABAA Receptors

  1997cited by this paper
• Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptor.

  1997cited by this paper
• 3 alpha-Hydroxy-3 beta-(phenylethynyl)-5 beta-pregnan-20-ones: synthesis and pharmacological activity of neuroactive steroids with high affinity for GABAA receptors.

  1997cited by this paper
• Modulation of amino acid-gated ion channels by protein phosphorylation.

  1996cited by this paper
• Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice.

  1996cited by this paper
• A putative receptor for neurosteroids on the GABAA receptor complex: the pharmacological properties and therapeutic potential of epalons.

  1995cited by this paper
• Anticonvulsant activity of neurosteroids: correlation with gamma-aminobutyric acid-evoked chloride current potentiation.

  1994cited by this paper
• Progesterone receptor-mediated effects of neuroactive steroids.

  1993cited by this paper
• Neurosteroids act on recombinant human GABAA receptors.

  1990cited by this paper
• Experimental Models of Temporal Lobe Epilepsy: New Insights from the Study of Kindling and Synaptic Reorganization

  1990cited by this paper
• Anticonvulsant profile of the progesterone metabolite 5 alpha-pregnan-3 alpha-ol-20-one.

  1989cited by this paper
• Anticonvulsant profile of the progesterone metabolite 5α-pregnan-3α-ol-20-one

  1989cited by this paper
• Structure-activity relationships for steroid interaction with the gamma-aminobutyric acidA receptor complex.

  1987cited by this paper
• Isolation of neurons suitable for patch-clamping from adult mammalian central nervous systems.

  1986cited by this paper
• Anticonvulsant drugs and their antagonism of kindled amygdaloid seizures in rats.

  1980cited by this paper
• Modification of seizure activity by electrical stimulation. 3. Mechanisms.

  1972cited by this paper
• Modification of seizure activity by electrical stimulation. II. Motor seizure.

  1972cited by this paper

• “The Interaction Between Oxidative Stress and Neurosteroid Imbalance in Multiple Sclerosis: Exploring a New Pathway in Disease Mechanisms and Potential Treatment Approaches”

  2026cites this paper
• Ganaxolone for the Treatment of CDKL5 Disorder and Other Neurological and Psychiatric Conditions: A Review of the Clinical Trials

  2025cites this paper
• Beyond Circadian Patterns: Mechanistic Insights into Sleep–Epilepsy Interactions and Therapeutic Implications

  2025cites this paper
• Synthesis and Evaluation of a Novel Zuranolone Analog with High GABAA Receptor PAM Activity and Excellent Pharmacokinetic Profiles

  2025cites this paper
• Decoding the structural and functional diversity of GABAA receptors: from ensemble logic to therapeutic opportunities

  2025cites this paper
• Neurosteroid mitigation of developmental neurological dysfunction, long-term epileptic biomarkers, chronic neuroinflammation, and neurodegeneration in a pediatric rat model of organophosphate exposure.

  2025cites this paper
• Early IGF-1 receptor inhibition in mice mimics preterm human brain disorders and reveals a therapeutic target

  2024cites this paper
• How Sex Hormones Affect Migraine: An Interdisciplinary Preclinical Research Panel Review

  2024cites this paper
• Cortical Tonic Inhibition Gates the Expression of Spike-and-Wave Discharges Associated with Absence Epilepsy.

  2024cites this paper
• Kindling Models of Epileptogenesis for Developing Disease‐Modifying Drugs for Epilepsy

  2024cites this paper
• Long‐term treatment with ganaxolone for seizures associated with cyclin‐dependent kinase‐like 5 deficiency disorder: Two‐year open‐label extension follow‐up

  2023cites this paper
• Long-Term Neuropsychiatric Developmental Defects after Neonatal Organophosphate Exposure: Mitigation by Synthetic Neurosteroids

  2023cites this paper
• Preclinical and clinical pharmacology of brexanolone (allopregnanolone) for postpartum depression: a landmark journey from concept to clinic in neurosteroid replacement therapy

  2023cites this paper
• Neuroprotectant Activity of Novel Water-Soluble Synthetic Neurosteroids on Organophosphate Intoxication and Status Epilepticus-Induced Long-Term Neurological Dysfunction, Neurodegeneration, and Neuroinflammation

  2023influential citation
• Protective Activity of Novel Hydrophilic Synthetic Neurosteroids on Organophosphate Status Epilepticus-induced Chronic Epileptic Seizures, Non-Convulsive Discharges, High-Frequency Oscillations, and Electrographic Ictal Biomarkers

  2023influential citation
• Neurosteroids as Novel Anticonvulsants for Refractory Status Epilepticus and Medical Countermeasures for Nerve Agents: A 15-Year Journey to Bring Ganaxolone from Bench to Clinic

  2023cites this paper
• Virally-induced expression of GABAA receptor δ subunits following their pathological loss reveals their role in regulating GABAA receptor assembly

  2022cites this paper
• Post-Traumatic Epilepsy and Comorbidities: Advanced Models, Molecular Mechanisms, Biomarkers, and Novel Therapeutic Interventions

  2022cites this paper
• Sex and Gender Considerations in Episodic Migraine

  2022cites this paper
• Intravenous ganaxolone for the treatment of refractory status epilepticus: Results from an open‐label, dose‐finding, phase 2 trial

  2022cites this paper
• Efficacy of the FDA-approved cannabidiol on the development and persistence of temporal lobe epilepsy and complex focal onset seizures.

  2022cites this paper
• Isobolographic analysis of adjunct antiseizure activity of the FDA-approved cannabidiol with neurosteroids and benzodiazepines in adult refractory focal onset epilepsy.

  2022cites this paper
• Neurosteroid replacement therapy for catamenial epilepsy, postpartum depression and neuroendocrine disorders in women

  2021cites this paper
• Does Stress Trigger Seizures? Evidence from Experimental Models.

  2021cites this paper
• Comparative profile of refractory status epilepticus models following exposure of cholinergic agents pilocarpine, DFP, and soman.

  2021cites this paper
• Extra-synaptic modulation of GABAA and efficacy in bipolar disorder.

  2021cites this paper
• Effective Activation by Kynurenic Acid and Its Aminoalkylated Derivatives on M-Type K+ Current

  2021cites this paper
• Allopregnanolone: An overview on its synthesis and effects

  2021cites this paper
• Neurosteroids

  2020cites this paper
• Anti-apoptotic Actions of Allopregnanolone and Ganaxolone Mediated Through Membrane Progesterone Receptors (PAQRs) in Neuronal Cells

  2020cites this paper
• Physiopathological role of the enzymatic complex 5α-reductase and 3α/β- hydroxysteroid oxidoreductase in the generation of progesterone and testosterone neuroactive metabolites.

  2020cites this paper
• Serum levels of allopregnanolone, progesterone and testosterone in menstrually-related and postmenopausal migraine: A cross-sectional study

  2020cites this paper
• Zinc reduces antiseizure activity of neurosteroids by selective blockade of extrasynaptic GABA‐A receptor‐mediated tonic inhibition in the hippocampus

  2019cites this paper
• Isobolographic Analysis of Antiseizure Activity of the GABA Type A Receptor-Modulating Synthetic Neurosteroids Brexanolone and Ganaxolone with Tiagabine and Midazolam

  2019influential citation
• Mechanism-based novel antidotes for organophosphate neurotoxicity.

  2019cites this paper
• Extrasynaptic γ‐aminobutyric acid type A receptor–mediated sex differences in the antiseizure activity of neurosteroids in status epilepticus and complex partial seizures

  2019cites this paper
• Neuroendocrine aspects of improving sleep in epilepsy.

  2018cites this paper