| Small molecule anticonvulsant agents with potent in vitro neuroprotection. | |
| | |
MedLine Citation:
|
PMID: 22535312 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Severe seizure activity is associated with recurring cycles of excitotoxicity and oxidative stress that result in progressive neuronal damage and death. Intervention to halt these pathological processes is a compelling disease-modifying strategy for the treatment of seizure disorders. In the present study, a core small molecule with anticonvulsant activity has been structurally optimized for neuroprotection. Phenotypic screening of rat hippocampal cultures with nutrient medium depleted of antioxidants was utilized as a disease model. Increased cell death and decreased neuronal viability produced by acute treatment with glutamate or hydrogen peroxide were prevented by our novel molecules. The neuroprotection associated with this chemical series has marked structure activity relationships that focus on modification of the benzylic position of a 2-phenyl-2-hydroxyethyl sulfamide core structure. Complete separation between anticonvulsant activity and neuroprotective action was dependent on substitution at the benzylic carbon. Chiral selectivity was evident in that the S-enantiomer of the benzylic hydroxy group had neither neuroprotective nor anticonvulsant activity, while the R-enantiomer of the lead compound had full neuroprotective action at <40 nM and antiseizure activity in three animal models. These studies indicate that potent, multifunctional neuroprotective anticonvulsants are feasible within a single molecular entity. |
| | |
Authors:
|
Douglas E Brenneman; Garry R Smith; Yan Zhang; Yanming Du; Sandeep K Kondaveeti; Michael J Zdilla; Allen B Reitz |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural Date: 2012-04-26 |
Journal Detail:
|
Title: Journal of molecular neuroscience : MN Volume: 47 ISSN: 1559-1166 ISO Abbreviation: J. Mol. Neurosci. Publication Date: 2012 Jun |
Date Detail:
|
Created Date: 2012-05-28 Completed Date: 2013-03-26 Revised Date: 2013-04-16 |
Medline Journal Info:
|
Nlm Unique ID: 9002991 Medline TA: J Mol Neurosci Country: United States |
Other Details:
|
Languages: eng Pagination: 368-79 Citation Subset: IM |
Affiliation:
|
Advanced Neural Dynamics, Inc., Pennsylvania Biotechnology Center, Doylestown, PA 18902, USA. dbrenneman@advneuraldynamics.com |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Anticonvulsants / chemistry, pharmacology* Caco-2 Cells Cells, Cultured Disease Models, Animal Epilepsy / drug therapy*, pathology Hippocampus / cytology, drug effects Humans Mice Neurons / drug effects*, pathology Neuroprotective Agents / chemistry, pharmacology* Rats Sulfonamides / chemistry, pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
|
R43 NS066537/NS/NINDS NIH HHS; R43NS066537/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Anticonvulsants; 0/Neuroprotective Agents; 0/Sulfonamides |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Computational fluid dynamics of developing avian outflow tract heart valves.
Next Document: The Role of Munc18-1 and Its Orthologs in Modulation of Cortical F-Actin in Chromaffin Cells.