Linked Life Data

19747831

Source:http://linkedlifedata.com/resource/pubmed/id/19747831

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
19
pubmed:dateCreated
2009-9-16
pubmed:abstractText
Voltage gated sodium channels represent an important therapeutic target for a number of neurological disorders including epilepsy. Unfortunately, medicinal chemistry strategies for discovering new classes of antagonist for trans-membrane ion channels have been limited to mostly broad screening compound arrays. We have developed new sodium channel antagonist based on a propofol scaffold using the ligand based strategy of comparative molecular field analysis (CoMFA). The resulting CoMFA model was correlated and validated to provide insights into the design of new antagonists and to prioritize synthesis of these new structural analogs (compounds 4 and 5) that satisfied the steric and electrostatic model. Compounds 4 and 5 were evaluated for [(3)H]-batrachotoxinin-A-20-alpha-benzoate ([(3)H]-BTX-B) displacement yielding IC(50)'s of 22 and 5.7 microM, respectively. We further examined the potency of these two compounds to inhibit neuronal sodium currents recorded from cultured hippocampal neurons. At a concentration of 50 microM, compounds 4 and 5 tonically inhibited sodium channels currents by 59+/-7.8% (n=5) and 70+/-7.5% (n=7), respectively. This clearly demonstrates that these compounds functionally antagonize native neuronal sodium channel currents. In summary, we have shown that CoMFA can be effectively used to discover new classes of sodium channel antagonists.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1464-3391
pubmed:author
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
17
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
7056-63
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Comparative molecular field analysis and synthetic validation of a hydroxyamide-propofol binding and functional block of neuronal voltage-dependent sodium channels.
pubmed:affiliation
Department of Oncology, 3970 Reservoir Road, Georgetown University Medical Center, Washington, DC 20057, USA. mb544@georgetown.edu
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural