Abstract
Piriqualone (1) was found to be an antagonist of AMPA receptors. Structure activity optimization was conducted on each of the three rings in 1 to afford a series of potent and selective antagonists. The sterically crowded environment surrounding the N-3 aryl group provided sufficient thermal stability for atropisomers to be isolated. Separation of these atropisomers resulted in the identification of (+)-38 (CP-465,022), a compound that binds to the AMPA receptor with high affinity (IC50 = 36 nM) and displays potent anticonvulsant activity.
MeSH terms
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Animals
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Anticonvulsants / chemical synthesis
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Anticonvulsants / chemistry
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Anticonvulsants / pharmacology
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Binding, Competitive
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Brain / metabolism
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Brain / physiology
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Calcium / pharmacokinetics
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Disease Models, Animal
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Inhibitory Concentration 50
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Isomerism
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Neuromuscular Blocking Agents / chemical synthesis
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Neuromuscular Blocking Agents / chemistry
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Neuromuscular Blocking Agents / pharmacology
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Protein Binding
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Pyridines
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Quinazolines / chemical synthesis
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Quinazolines / chemistry
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Quinazolines / pharmacology*
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Quinazolinones
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Rats
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Receptors, AMPA / antagonists & inhibitors*
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Seizures / chemically induced
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Seizures / drug therapy
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Solubility
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Structure-Activity Relationship
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Synaptic Transmission / drug effects
Substances
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Anticonvulsants
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Neuromuscular Blocking Agents
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Pyridines
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Quinazolines
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Quinazolinones
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Receptors, AMPA
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piriqualone
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Calcium