Abstract
A series of substituted 1-hydroxypyrazole analogues of the GABA(A) receptor partial agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL) have been synthesized and pharmacologically characterized. Several of the analogues displayed K(i) in the low nanomolar range at the native GABA(A) receptors and potent antagonism of the alpha(1)beta(2)gamma(2) receptor. It appears that several regions situated in proximity to the core of the orthosteric binding site of the GABA(A) receptor are able to accommodate large hydrophobic substituents.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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GABA Antagonists / chemical synthesis*
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GABA Antagonists / chemistry
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GABA Antagonists / pharmacology
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GABA Uptake Inhibitors
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Humans
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Hydrophobic and Hydrophilic Interactions
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In Vitro Techniques
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Ligands
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Membrane Potentials / drug effects
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Models, Molecular
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Rats
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Receptors, GABA-A / metabolism*
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Structure-Activity Relationship
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Synaptic Membranes / drug effects
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Synaptic Membranes / physiology
Substances
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GABA Antagonists
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GABA Uptake Inhibitors
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Ligands
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Piperidines
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Pyrazoles
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Receptors, GABA-A