title: 4-Aminoquinolines: novel nociceptin antagonists with analgesic activity.
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.
authors: Central Pharmaceutical Research Institute, JT Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. hisashi.shinkai@ims.jti.co.jp
authors: H
authors: H
authors: Shinkai
authors: T
authors: T
authors: Ito
authors: T
authors: T
authors: Iida
authors: Y
authors: Y
authors: Kitao
authors: H
authors: H
authors: Yamada
authors: I
authors: I
authors: Uchida
mesh_terms: D000249:Adenosine Monophosphate / Q000096:biosynthesis; D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018847:Opioid Peptides / Q000037:antagonists & inhibitors*; D010147:Pain Measurement; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013329:Structure-Activity Relationship; D000097629:Nociceptin
chemical_list: D000249:Adenosine Monophosphate; D000634:Aminoquinolines; D000700:Analgesics; D001549:Benzamides; D009270:Naloxone; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D000097629:Nociceptin; C433236:N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide