Abstract
Background & Objective: 6-[(1S)-1-[1-[5-(2-hydroxyethoxy)-2-pyridyl]pyrazol-3-yl]ethyl]- 3H-1,3-benzothiazol-2-one (LY3130481 or CERC-611) is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor regulatory protein (TARP) γ-8 that is under development for epilepsy. The present study provided a broad inquiry into its anticonvulsant properties. LY3130481 was anticonvulsant in multiple acute seizure provocation models in mice and rats. In addition, LY3130481 was effective against absence seizures in the GAERS genetic model and in the Frings mouse model. Likewise, LY3130481 attenuated convulsions in mice and rats with long-term induction of seizures (e.g., corneal, pentylenetetrazole, hippocampal, and amygdala kindled seizures). In slices of epileptic human cortex, LY3130481 significantly decreased neuronal firing frequencies. LY3130481 displaced from rat brain a radioligand specific for AMPA receptors associated with TARP γ-8 whereas non-TARP-selective molecules did not. Binding was also observed in hippocampus freshly transected from a patient.
Results & Conclusion: Taken as a whole, the findings reported here establish the broad anticonvulsant efficacy of LY3130481 indicating that blockade of AMPA receptors associated with TARP γ-8 is sufficient for these protective effects.
Keywords: AMPA receptors, antagonist, anticonvulsant activity, CERC-611, LY3130481, TARP-g8, transmembrane.
CNS & Neurological Disorders - Drug Targets
Title:Targeted Blockade of TARP-γ8-Associated AMPA Receptors: Anticonvulsant Activity with the Selective Antagonist LY3130481 (CERC-611)
Volume: 16 Issue: 10
Author(s): Jeffrey M. Witkin*, Douglas A. Schober, Scott D. Gleason, John T. Catlow, Warren J. Porter, Jon Reel, Xiaoming Jin, Jonathan Hobbs, Donald Gehlert, Douglas L. Gernert, Kevin M. Gardinier, Akihiko S. Kato, Xingjie Ping and Jodi L. Smith
Affiliation:
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana,United States
Keywords: AMPA receptors, antagonist, anticonvulsant activity, CERC-611, LY3130481, TARP-g8, transmembrane.
Abstract: Background & Objective: 6-[(1S)-1-[1-[5-(2-hydroxyethoxy)-2-pyridyl]pyrazol-3-yl]ethyl]- 3H-1,3-benzothiazol-2-one (LY3130481 or CERC-611) is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor regulatory protein (TARP) γ-8 that is under development for epilepsy. The present study provided a broad inquiry into its anticonvulsant properties. LY3130481 was anticonvulsant in multiple acute seizure provocation models in mice and rats. In addition, LY3130481 was effective against absence seizures in the GAERS genetic model and in the Frings mouse model. Likewise, LY3130481 attenuated convulsions in mice and rats with long-term induction of seizures (e.g., corneal, pentylenetetrazole, hippocampal, and amygdala kindled seizures). In slices of epileptic human cortex, LY3130481 significantly decreased neuronal firing frequencies. LY3130481 displaced from rat brain a radioligand specific for AMPA receptors associated with TARP γ-8 whereas non-TARP-selective molecules did not. Binding was also observed in hippocampus freshly transected from a patient.
Results & Conclusion: Taken as a whole, the findings reported here establish the broad anticonvulsant efficacy of LY3130481 indicating that blockade of AMPA receptors associated with TARP γ-8 is sufficient for these protective effects.
Export Options
About this article
Cite this article as:
Witkin M. Jeffrey *, Schober A. Douglas, Gleason D. Scott , Catlow T. John , Porter J. Warren , Reel Jon , Jin Xiaoming, Hobbs Jonathan, Gehlert Donald, Gernert L. Douglas , Gardinier M. Kevin , Kato S. Akihiko, Ping Xingjie and Smith L. Jodi, Targeted Blockade of TARP-γ8-Associated AMPA Receptors: Anticonvulsant Activity with the Selective Antagonist LY3130481 (CERC-611), CNS & Neurological Disorders - Drug Targets 2017; 16 (10) . https://dx.doi.org/10.2174/1871527316666171101132047
DOI https://dx.doi.org/10.2174/1871527316666171101132047 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
Call for Papers in Thematic Issues
Diagnosis and treatment of central nervous system infectious diseases
Infectious diseases of the central nervous system (CNS) can be divided into bacterial, tuberculous, viral, fungal, parasitic infections, etc. Early etiological treatment is often the most crucial means to reduce the mortality rate of patients with central nervous system infections, reduce complications and sequelae, and improve prognosis. The initial clinical ...read more
Techniques of Drug Repurposing: Delivering a new life to Herbs & Drugs
Of late, with the adaptation of innovative approaches and integration of advancements made towards medical sciences as well as the availability of a wide range of tools; several therapeutic challenges are being translated into viable clinical solutions, with a high degree of efficacy, safety, and selectivity. With a better understanding ...read more
Trends and perspectives in the rational management of CNS disorders
Central nervous system (CNS) diseases enforce a significant global health burden, driving ongoing efforts to improve our understanding and effectiveness of therapy. This issue investigates current advances in the discipline, focusing on the understanding as well as therapeutic handling of various CNS diseases. The issue covers a variety of diseases, ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Focus on the Role of Glutamate in the Pathology of the Peripheral Nervous System
CNS & Neurological Disorders - Drug Targets The Microbial Quality Aspects and Decontamination Approaches for the Herbal Medicinal Plants and Products: An in-Depth Review
Current Pharmaceutical Design Shilajit (Mumie): Current Status of Biochemical, Therapeutic and Clinical Advances
Current Nutrition & Food Science Efficacy and Tolerability of Lacosamide for Focal Epileptic Patients: Study from Epilepsy Clinic in Makkah
CNS & Neurological Disorders - Drug Targets A Comparative Study of the CYP450 Inhibition Potential of Marketed Drugs Using Two Fluorescence Based Assay Platforms Routinely Used in the Pharmaceutical Industry
Drug Metabolism Letters Metabolic Profiling in Multiple Sclerosis and Other Disorders by Quantitative Analysis of Cerebrospinal Fluid Using Nuclear Magnetic Resonance Spectroscopy
Current Pharmaceutical Biotechnology GABA System as a Target for New Drugs
Current Medicinal Chemistry Beta-blockers in the Perioperative Period: Are there Indications other than Prevention of Cardiac Ischemia?
Current Drug Targets Biophysical Modeling and Associated Signal Modeling in Functional Magnetic Resonance Imaging
Neuroscience and Biomedical Engineering (Discontinued) Serpin Regulation of Fibrinolytic System: Implications for Therapeutic Applications in Cardiovascular Diseases
Cardiovascular & Hematological Agents in Medicinal Chemistry Crosstalk Between Calpain and Calcineurin in Excitotoxic Neurodegeneration; Therapeutic Targets for the Treatment of Excitotoxic Neurodegeneration
Current Medicinal Chemistry - Central Nervous System Agents Management of Incidental Findings in the Era of Next-generation Sequencing
Current Genomics Therapeutic Role of Zonisamide in Neuropsychiatric Disorders
Mini-Reviews in Medicinal Chemistry Rationale Design, Synthesis, and Pharmacological Evaluation of Isatin Analogues as Antiseizure Agents
Letters in Drug Design & Discovery Truly “Rational” Polytherapy: Maximizing Efficacy and Minimizing Drug Interactions, Drug Load, and Adverse Effects
Current Neuropharmacology Aptamers as Tools to Study Dysfunction in the Neuronal System
Current Medicinal Chemistry - Central Nervous System Agents Pharmacogenomics of Cardiovascular Complications in Diabetes and Obesity
Recent Patents on Biotechnology Cardiac ATP-Sensitive Potassium Channels: A Potential Target for an Anti-Ischaemic Pharmacological Strategy
Cardiovascular & Hematological Agents in Medicinal Chemistry Concise Synthesis of Non-Protein Amino Acid from Natural Product via Schmidt Reaction
Letters in Organic Chemistry Cannabinoids
Current Drug Targets - CNS & Neurological Disorders