ArticleThe Journal of pharmacology and experimental therapeutics2016
Neurosteroid Structure-Activity Relationships for Functional Activation of Extrasynaptic δGABA(A) Receptors.
Article in The Journal of pharmacology and experimental therapeutics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 77 citations in OpenAlex.
- Article
- Progesterone- and deoxycorticosterone-derived GABAergic neurosteroids induce itch-related scratching behavior in mouse model of atopic dermatitis.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- Neurosteroid mitigation of developmental neurological dysfunction, long-term epileptic biomarkers, chronic neuroinflammation, and neurodegeneration in a pediatric rat model of organophosphate exposure.The Journal of pharmacology and experimental therapeutics · 2025Article
- Synthesis and Evaluation of a Novel Zuranolone Analog with High GABAMolecules (Basel, Switzerland) · 2025Article
- Neurosteroids: a lifelong impact on brain health.Frontiers in behavioral neuroscience · 2025Review
- Decoding the structural and functional diversity of GABAFrontiers in pharmacology · 2025Review
- Neuroprotectant Activity of Novel Water-Soluble Synthetic Neurosteroids on Organophosphate Intoxication and Status Epilepticus-Induced Long-Term Neurological Dysfunction, Neurodegeneration, and Neuroinflammation.The Journal of pharmacology and experimental therapeutics · 2024Article
- 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.The Journal of pharmacology and experimental therapeutics · 2024Article
- 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.The Journal of pharmacology and experimental therapeutics · 2024Review
- Long-Term Neuropsychiatric Developmental Defects after Neonatal Organophosphate Exposure: Mitigation by Synthetic Neurosteroids.The Journal of pharmacology and experimental therapeutics · 2024Article
- Neuroendocrine insights into neurosteroid therapy for postpartum depression.Trends in molecular medicine · 2023Article
- Preclinical and clinical pharmacology of brexanolone (allopregnanolone) for postpartum depression: a landmark journey from concept to clinic in neurosteroid replacement therapy.Psychopharmacology · 2023Review
- Neurosteroid influence on affective tone.Neuroscience and biobehavioral reviews · 2023Review
- Neurosteroids Mediate Neuroprotection in an In Vitro Model of Hypoxic/Hypoglycaemic Excitotoxicity via δ-GABAInternational journal of molecular sciences · 2023Article
- Article
- Isobolographic analysis of adjunct antiseizure activity of the FDA-approved cannabidiol with neurosteroids and benzodiazepines in adult refractory focal onset epilepsy.Experimental neurology · 2023Article
- Non-sedative cortical EEG signatures of allopregnanolone and functional comparators.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2023Article
- Novel Therapeutics for Treating Sleep Disorders: New Perspectives onInternational journal of molecular sciences · 2022Article
- Allosteric modulators of the δ GABANeuropharmacology · 2022Article
- The Influence of AA29504 on GABANeurochemical research · 2022Article
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Synaptic GABAA receptors are primary mediators of rapid inhibition in the brain and play a key role in the pathophysiology of epilepsy and other neurologic disorders. The δ-subunit GABAA receptors are expressed extrasynaptically in the dentate gyrus and contribute to tonic inhibition, promoting network shunting as well as reducing seizure susceptibility. However, the neurosteroid structure-function relationship at δGABA(A) receptors within the native hippocampus neurons remains unclear. Here we report a structure-activity relationship for neurosteroid modulation of extrasynaptic GABAA receptor-mediated tonic inhibition in the murine dentate gyrus granule cells. We recorded neurosteroid allosteric potentiation of GABA as well as direct activation of tonic currents using a wide array of natural and synthetic neurosteroids. Our results shows that, for all neurosteroids, the C3α-OH group remains obligatory for extrasynaptic receptor functional activity, as C3β-OH epimers were inactive in activating tonic currents. Allopregnanolone and related pregnane analogs exhibited the highest potency and maximal efficacy in promoting tonic currents. Alterations at the C17 or C20 region of the neurosteroid molecule drastically altered the transduction kinetics of tonic current activation. The androstane analogs had the weakest modulatory response among the analogs tested. Neurosteroid potentiation of tonic currents was completely (approximately 95%) diminished in granule cells from δ-knockout mice, suggesting that δ-subunit receptors are essential for neurosteroid activity. The neurosteroid sensitivity of δGABA(A) receptors was confirmed at the systems level using a 6-Hz seizure test. A consensus neurosteroid pharmacophore model at extrasynaptic δGABA(A) receptors is proposed based on a structure-activity relationship for activation of tonic current and seizure protection.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.