Abstract
Series of compounds were generated via the bioisosteric replacement of the carboxylate of 4-ACPCA (2) with hydroxamate or amide groups. All compounds from this study exhibited increased selectivity for GABAC, the most potent being 4-ACPHA (10a, IC50 = 13 μM) and 4-ACPAM (11a, IC50 = 10 μM). This provides evidence that a zwitterionic structure is not essential for GABAC antagonists, rather the emphasis lies in appropriate heteroatoms to participate in hydrogen bonding.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / chemical synthesis
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Amides / chemistry
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Amides / pharmacology
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Animals
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Binding, Competitive
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Chemistry, Pharmaceutical / methods*
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Cyclopentanes / chemistry
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Cyclopentanes / pharmacology
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Female
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GABA Antagonists / chemistry*
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GABA Antagonists / pharmacology*
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Humans
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Hydroxamic Acids / chemical synthesis
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Hydroxamic Acids / chemistry
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Hydroxamic Acids / pharmacology
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Membrane Potentials / drug effects
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Models, Chemical
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Models, Molecular
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Molecular Structure
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Oocytes / drug effects
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Oocytes / metabolism
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Oocytes / physiology
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Patch-Clamp Techniques
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Protein Structure, Tertiary
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Receptors, GABA / chemistry
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Receptors, GABA / genetics
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Receptors, GABA / metabolism*
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Xenopus laevis
Substances
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Amides
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Cyclopentanes
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GABA Antagonists
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GABA-C receptor
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Hydroxamic Acids
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Receptors, GABA