4-aminoquinolines: Novel nociceptin antagonists with analgesic activity

Small-molecule nociceptin antagonists were synthesized to examine their the rapeutic potential. After a 4-aminoquinoline derivative was found to bind w ith the human ORL1 receptor, a series of 4-aminoquinolines and related comp ounds were synthesized and their binding was evaluated. Elucidation of stru cture-activity relationships eventually led to the optimum compounds. One o f the se compounds, N-(4-amino-2-methylquinolin-6-yl) -2-(4-ethylphenoxymet hyl)benzamide hydrochloride (11) not only antagonized nociceptin-induced al lodynia 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 antago nized by the opioid antagonist naloxone. These results indicate that this n ociceptin antagonist has the potential to become a novel type of analgesic that differs from mu -opioid agonists.