Pharmacological properties of a novel nociceptin/orphanin FQ receptor agonist, 2-(3,5-dimethylpiperazin-1-yl)-1-[1-(1-methylcyclooctyl)piperidin-4-yl]-1H-benzimidazole, with anxiolytic potential.

We have characterized the pharmacological properties of the novel nociceptin/orphanin FQ peptide receptor (NOP receptor) agonist, 2-(3,5-dimethylpiperazin-1-yl)-1-[1-(1-methylcyclooctyl)piperidin-4-yl]-1H-benzimidazole (PCPB). PCPB bound to the NOP receptor in mouse brain membranes (Ki=0.12 nM) and to recombinant human NOP receptor (Ki=2.1 nM). PCPB showed full agonism for the NOP receptor in isolated mouse vas deferens with a maximal effect and high potency that were similar to the pharmacological profile observed for nociceptin/orphanin FQ (N/OFQ) (pD(2): 6.9+/-0.2; 95+/-2% activity). Orally administered PCPB (30 mg/kg) penetrated well into the brains of the mice. PCPB exhibited an anxiolytic activity in mice subjected to the Vogel conflict test that was comparable to the maximal response induced by diazepam, a representative anxiolytic agent. The anxiolytic effect of PCPB was dose-dependently blocked by the NOP receptor antagonist, J-113397, demonstrating that this effect was mediated by the NOP receptor agonist activity. Behavioral studies in mice also showed that PCPB prolonged the pentobarbital-induced sleeping time but did not cause muscle relaxation at the oral anxiolytic dose of 30 mg/kg. Unlike diazepam, however, these central effects of PCPB were weak. Our results indicate that PCPB is a potent anxiolytic agent with agonistic activities for the NOP receptor.