Abstract
Small-molecule nociceptin antagonists were synthesized to examine their therapeutic potential. After a 4-aminoquinoline derivative was found to bind with the human ORL(1) receptor, a series of 4-aminoquinolines and related compounds were synthesized and their binding was evaluated. Elucidation of structure-activity relationships eventually led to the optimum compounds. One of these compounds, N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide hydrochloride (11) not only antagonized nociceptin-induced allodynia in mice but also showed analgesic effect in a hot plate test using mice and in a formalin test using rats. Its analgesic effect was not antagonized by the opioid antagonist naloxone. These results indicate that this nociceptin antagonist has the potential to become a novel type of analgesic that differs from mu-opioid agonists.
MeSH terms
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Adenosine Monophosphate / biosynthesis
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Aminoquinolines / chemical synthesis*
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Aminoquinolines / chemistry
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Aminoquinolines / pharmacology
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Analgesics / chemical synthesis*
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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Benzamides / chemical synthesis*
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Benzamides / chemistry
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Benzamides / pharmacology
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Cell Line
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Drug Evaluation, Preclinical
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Humans
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Male
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Mice
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Mice, Inbred ICR
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Naloxone / pharmacology
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Narcotic Antagonists / chemical synthesis*
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Narcotic Antagonists / chemistry
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Narcotic Antagonists / pharmacology
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Nociceptin
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Opioid Peptides / antagonists & inhibitors*
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Pain Measurement
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Radioligand Assay
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Receptors, Opioid, delta / metabolism
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Receptors, Opioid, kappa / metabolism
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Receptors, Opioid, mu / metabolism
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Structure-Activity Relationship
Substances
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Aminoquinolines
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Analgesics
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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, delta
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Receptors, Opioid, kappa
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Receptors, Opioid, mu
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Naloxone
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Adenosine Monophosphate