Abstract
A focused library approach identifying novel leads to develop a potent ORL1 antagonist is described. Beginning from a compound identified by random screening, an exploratory library that exhibited a diverse display of pharmacophores was designed. After evaluating ORL1 antagonistic activity, a highly focused library was designed based on 3D-pharmacophore similarity to known actives. A novel D-proline amide class was identified in this library and was found to possess potent ORL1 antagonistic activity.
MeSH terms
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Animals
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Binding, Competitive
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CHO Cells
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Combinatorial Chemistry Techniques
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Cricetinae
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Cricetulus
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Humans
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Hydrophobic and Hydrophilic Interactions
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Models, Molecular
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Molecular Structure
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Narcotic Antagonists*
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Nociceptin Receptor
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Proline / analogs & derivatives
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Proline / chemical synthesis
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Proline / chemistry
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Proline / pharmacology
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Quantitative Structure-Activity Relationship
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Radioligand Assay
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Receptors, Opioid / agonists
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Receptors, Opioid / chemistry*
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Spiro Compounds / chemical synthesis*
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Spiro Compounds / chemistry
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Spiro Compounds / pharmacology
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Stereoisomerism
Substances
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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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Proline
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prolinamide
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Nociceptin Receptor