Abstract
Based on reported structures, a focused library of biarylmethyl bound to the nitrogen atom of spiropiperidine was designed. Systematic modifications allowed the discovery of a synthetically feasible and highly potent ORL1 antagonist 37, 1'-{[1-(3-chloropyridin-2-yl)-1H-pyrazol-4-yl]methyl}-3H-spiro[2-benzofuran-1,4'-piperidine], which exhibits excellent selectivity to mu, kappa, and human ether-a-go-go related gene potassium channel.
MeSH terms
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Binding, Competitive
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Chemistry, Pharmaceutical / methods*
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Drug Design
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / metabolism
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Humans
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Inhibitory Concentration 50
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Models, Chemical
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Molecular Conformation
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Molecular Structure
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Narcotic Antagonists*
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Nociceptin Receptor
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Piperidines / chemistry*
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Protein Binding
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Receptors, Opioid
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Spiro Compounds / chemistry*
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Structure-Activity Relationship
Substances
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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KCNH2 protein, human
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Narcotic Antagonists
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Piperidines
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Receptors, Opioid
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Spiro Compounds
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piperidine
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Nociceptin Receptor
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OPRL1 protein, human