Abstract
A series of 4-amino-2-methylquinoline and 4-aminoquinazoline derivatives, including the reference NOP antagonist JTC-801, were synthesized by an alternative pathway and their in vitro pharmacological properties were investigated. 3-Substitution of the quinoline ring resulted very critical for affinity. So 3-methyl derivative 4j showed a similar potency compared with the reference 4h while bulky lipophilic or electron withdrawing groups in the same position strongly decreased affinity. Structural and conformational requirements for affinity were outlined by NOE NMR and computational methods and suggestions for a pharmacophore model design were provided.
MeSH terms
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Aminoquinolines / chemical synthesis*
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Aminoquinolines / chemistry
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Aminoquinolines / metabolism
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Aminoquinolines / pharmacology
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Benzamides / chemical synthesis*
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Benzamides / chemistry
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Benzamides / metabolism
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Benzamides / pharmacology
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Binding, Competitive
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Calorimetry
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Dose-Response Relationship, Drug
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GTP-Binding Proteins / metabolism
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Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
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Humans
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In Vitro Techniques
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Logistic Models
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Molecular Conformation
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Molecular Structure
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Narcotic Antagonists*
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Nociceptin
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Nociceptin Receptor
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Opioid Peptides / metabolism
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Protein Binding
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Receptors, Opioid / metabolism
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Structure-Activity Relationship
Substances
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Aminoquinolines
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Benzamides
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N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide
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Narcotic Antagonists
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Opioid Peptides
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Receptors, Opioid
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Guanosine 5'-O-(3-Thiotriphosphate)
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GTP-Binding Proteins
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Nociceptin Receptor
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OPRL1 protein, human