In vitro characterization of J-113397, a non-peptide nociceptin/orphanin FQ receptor antagonist.

The lack of availability of a selective, highly potent, competitive antagonist for the nociceptin receptor (OP₄) devoid of residual agonistic activity has hampered studies in this area. We report here the in vitro pharmacological properties of the novel non-peptide OP₄ antagonist, J-113397, which was recently discovered by Banyu Pharmaceutical investigators. The compound was synthesized as a racemic mixture in our laboratories. J-113397 was shown to antagonize (pA₂ 7.52) the nociceptin-induced inhibition of cAMP formation in cells expressing the recombinant human OP₄ receptor (CHO_hOP4) and to displace [¹²⁵I]Tyr¹⁴nociceptin from CHO_hOP4 membranes with a pK_i of 8.56. It also competitively antagonized the contractile actions of nociceptin in the mouse colon (pA₂ 8.07) and the inhibitory effect of nociceptin in electrically stimulated preparations such as the mouse vas deferens (pA₂ 7.85), the guinea pig ileum (7.75), and the rat vas deferens (7.77). At high concentrations (10 µM), the compound was devoid of agonist activity in the mouse vas deferens and CHO_hOP4, while it contracted the mouse colon and increased the twitch response of the rat vas deferens, and produced a naloxone-sensitive inhibition of the electrically evoked twitches in the guinea pig ileum. pA₂ values for the new antagonist against deltorphin I in the mouse vas deferens (OP₁ receptors), or against dermorphin in the guinea pig ileum (OP₃ receptors), etorphine in the rat vas deferens (OP receptors), U69593 in the rabbit vas deferens (OP₂ receptors) and endomorphin 1 in the mouse colon (OP₃ receptors) were lower than 6. Taken together, these data indicate that J-113397 is a high-affinity, selective and competitive antagonist of the OP₄ receptor; this novel pharmacological tool will be of great value in studies directed at evaluating the physiological roles of the nociceptin/OP₄ system. [ABSTRACT FROM AUTHOR]