Abstract
A multi-disciplinary approach was used to identify the first pharmacophore model for KCC2 blockers: several physico-chemical studies such as XRD and NMR were combined to molecular modelling techniques, SAR analysis and synthesis of constrained analogues in order to determine a minimal conformational space regrouping few potential bioactive conformations. These conformations were further compared to the conformational space of a different series of KCC2 blockers in order to identify the common pharmacophoric features. The synthesis of more potent analogues in this second series confirmed the usefulness of this KCC2 blocker pharmacophore model.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anticonvulsants / chemical synthesis*
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Anticonvulsants / pharmacology
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Cell Line, Tumor
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Furosemide / pharmacology
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High-Throughput Screening Assays
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Humans
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Ion Transport / drug effects
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K Cl- Cotransporters
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Magnetic Resonance Spectroscopy
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Models, Molecular
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Molecular Conformation
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Potassium Channel Blockers / chemical synthesis*
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Potassium Channel Blockers / pharmacology
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Proline / analogs & derivatives*
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Proline / chemical synthesis*
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Proline / pharmacology
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Rats
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Structure-Activity Relationship
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Symporters / antagonists & inhibitors*
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Symporters / metabolism
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X-Ray Diffraction
Substances
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Anticonvulsants
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Potassium Channel Blockers
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Symporters
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Furosemide
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Proline