A potent and highly selective nonpeptidyl nociceptin/orphanin FQ receptor (ORL1) antagonist: J-113397

We discovered a potent nociceptin/orphanin FQ receptor (ORL1) receptor anta gonist, J-113397 (1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl ]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one). J-113397 inhibited [I-125][Ty r(14)]nociceptin binding to Chinese hamster ovary (CHO) cells expressing OR L1 receptor in a dose-dependent manner (IC50; 2.3 nM), but showed 600-fold or less affinity for mu-, delta- and kappa-opioid receptors. Nociceptin/orp hanin FQ-induced suppression of cyclic AMP accumulation elicited by forskol in was completely inhibited by J-113397 with an IC50 value of 26 nM. These results indicate that J-113397 is a potent and selective nonpeptidyl antago nist of the ORL1 receptor. (C) 2000 Elsevier Science B.V. All rights reserv ed.