Linked Life Data

19346132

Source:http://linkedlifedata.com/resource/pubmed/id/19346132

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
19
pubmed:dateCreated
2009-9-16
pubmed:abstractText
The voltage-gated sodium channel remains a rich area for the development of novel blockers. In this study we used comparative molecular field analysis (CoMFA), a ligand-based design strategy, to generate a 3D model based upon local anesthetics, hydantoins, and alpha-hydroxyphenylamides to elucidate a SAR for their binding site in the neuronal sodium channel. Correlation by partial least squares (PLS) analysis of in vitro sodium channel binding activity (expressed as pIC(50)) and the CoMFA descriptor column generated a final non-cross-validated model with q(2)=0.926 for the training set. The CoMFA steric and electrostatic maps described a binding site predominately hydrophobic in nature. This model was then used to design and predict a series of novel sodium channel blockers that utilized overlapping structural features of phenytoin, hydroxy amides, and the local anesthetic lidocaine. Synthesis and evaluation of these compounds for their ability to inhibit [(3)H]-batrachotoxin revealed that these compounds have potent sodium channel blockade. Furthermore, the CoMFA model was able to accurately predict the binding of these compounds to the neuronal sodium channel. Synthesis and subsequent sodium channel evaluation of compound 37 (predicted IC(50)=7 microM, actual IC(50)=6 microM), established that novel compounds based on overlapping regions of phenytoin and lidocaine are better binders to the sodium channel than phenytoin itself (IC(50)=40 microM).
pubmed:grant
pubmed:commentsCorrections
http://linkedlifedata.com/resource/pubmed/commentcorrection/19346132-10229624, http://linkedlifedata.com/resource/pubmed/commentcorrection/19346132-10753468, http://linkedlifedata.com/resource/pubmed/commentcorrection/19346132-11024055, http://linkedlifedata.com/resource/pubmed/commentcorrection/19346132-11181979, http://linkedlifedata.com/resource/pubmed/commentcorrection/19346132-11306693, http://linkedlifedata.com/resource/pubmed/commentcorrection/19346132-12130650, http://linkedlifedata.com/resource/pubmed/commentcorrection/19346132-18411331, http://linkedlifedata.com/resource/pubmed/commentcorrection/19346132-19346132, http://linkedlifedata.com/resource/pubmed/commentcorrection/19346132-2437590, http://linkedlifedata.com/resource/pubmed/commentcorrection/19346132-2579237, http://linkedlifedata.com/resource/pubmed/commentcorrection/19346132-7932556, http://linkedlifedata.com/resource/pubmed/commentcorrection/19346132-8799190, http://linkedlifedata.com/resource/pubmed/commentcorrection/19346132-9046351, http://linkedlifedata.com/resource/pubmed/commentcorrection/19346132-9765515
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
7064-72
pubmed:dateRevised
2011-7-22
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Ligand-based design and synthesis of novel sodium channel blockers from a combined phenytoin-lidocaine pharmacophore.
pubmed:affiliation
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural