4-Aminoquinolines: Novel Nociceptin
Antagonists with Analgesic Activity
by
Shinkai H, Ito T, Iida T, Kitao Y, Yamada H, Uchida I
Central Pharmaceutical Research Institute,
JT Inc., 1-1 Murasaki-cho,
Takatsuki, Osaka 569-1125, Japan.
J Med Chem 2000 Nov 30; 43(24):4667-4677

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.

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