Pharmacological profiles of a novel opioid receptor-like1 (ORL1) receptor antagonist, JTC-801

1 Pharmacological effects of a novel opioid receptor-likel (ORL1) receptor antagonist, [N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride] (JTC-801), were examined in in vitro and in vivo. 2 JTC-801 inhibited the binding of [H-3]-nociceptin to human ORL1 receptors expressed in HeLa cells with a K-i value of 44.5 nm. 3 JTC-801 completely antagonized the suppression of nociceptin on forskolin-induced accumulation of cyclic AMP (IC50: 2.58 muM) using ORL1 receptor expressing HeLa cells in vitro. 4 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. 5 Effects of JTC-801 on various nociceptive models were examined. In mouse hot-plate test, JTC801 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. 6 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.). 7 We have demonstrated that JTC-801 antagonizes the ORL, 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.