title: Pharmacological profiles of a novel opioid receptor-like1 (ORL(1)) receptor antagonist, JTC-801.
abstract: Pharmacological effects of a novel opioid receptor-like1 (ORL(1)) receptor antagonist, [N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride] (JTC-801), were examined in in vitro and in vivo. JTC-801 inhibited the binding of [(3)H]-nociceptin to human ORL(1) receptors expressed in HeLa cells with a K(i) value of 44.5 nM. JTC-801 completely antagonized the suppression of nociceptin on forskolin-induced accumulation of cyclic AMP (IC(50) : 2.58 microM) using ORL(1) receptor expressing HeLa cells in vitro. In in vivo, when given intravenously at dosages of 0.01 mg kg(-1) and above, or orally at dosages 1 mg kg(-1) and above, JTC-801 antagonized the nociceptin-induced allodynia in mice. Effects of JTC-801 on various nociceptive models were examined. In mouse hot-plate test, JTC-801 prolonged escape response latency (ERL) to exposed heat stimulus with minimum effective doses (MED) of 0.01 mg kg(-1) by i.v. or 1 mg kg(-1) by p.o. In the rat formalin test, JTC-801 reduced both the first and second phases of the nociceptive response with MED of 0.01 mg kg(-1) by i.v. administration or 1 mg kg(-1) by p.o. administration. This anti-nociceptive action of JTC-801 was not inhibited by naloxone (10 mg kg(-1), s.c.). We have demonstrated that JTC-801 antagonizes the ORL(1) receptor response, and that JTC-801 has efficacious and potent anti-nociceptive effects in acute pain animal models not only by intravenous injection but also oral administration. These results suggest that JTC-801 may represent a new class of analgesics.
authors.affiliation: Central Pharmacological Research Institute, JT Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan. hideki.yamada@ims.jti.co.jp
authors.forename: Hideki
authors.initials: H
authors.lastname: Yamada
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakamoto
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Takao
authors.initials: T
authors.lastname: Ito
authors.forename: Kazuo
authors.initials: K
authors.lastname: Aisaka
mesh_terms: D000634:Aminoquinolines / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000378:metabolism* / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009292:Narcotic Antagonists / Q000378:metabolism* / Q000494:pharmacology*; D018847:Opioid Peptides / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000378:metabolism*; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D000634:Aminoquinolines; D001549:Benzamides; D000242:Cyclic AMP; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C433236:N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide