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

Pharmacological effects of a novel opioid receptor‐like1 (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. JTC‐801 inhibited the binding of [3H]‐nociceptin to human ORL1 receptors expressed in HeLa cells with a Ki value of 44.5 nM. JTC‐801 completely antagonized the suppression of nociceptin on forskolin‐induced accumulation of cyclic AMP (IC50 : 2.58 μM) using ORL1 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 ORL1 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. British Journal of Pharmacology (2002) 135, 323–332; doi:10.1038/sj.bjp.0704478