Discovery of small-molecule nonpeptide antagonists of nociceptin/orphanin FQ receptor: The studies of design, synthesis, and structure–activity relationships for (4-arylpiperidine substituted-methyl)-[bicyclic (hetero)cycloalkanobenzene] derivatives

• Novel small-molecule NOP receptor antagonists were designed, prepared, and evaluated.
• Compound 15 exhibited high potency and high selectivity as a NOP receptor antagonist.
• Contributing-factors for potency/selectivity of NOP receptor antagonist are suggested.
• Contributing-factors for metabolic stability are suggested.
• Contributing-factors for reducing hERG channel binding affinity are suggested.

Nociceptin/orphanin FQ (N/OFQ) and N/OFQ peptide (NOP) receptor are expressed and distributed in various regions such as central nervous system (CNS), peripheral nervous system, immune system, and peripheral tissues. N/OFQ and NOP receptor have important roles on a variety of physiological, pathophysiological, regulatory, and dysregulatory mechanisms in the living body. Both activation and blockade of NOP receptor function have displayed clinical potential of NOP receptor agonists and antagonists for the treatment of various diseases or pathophysiological conditions, respectively. Potent and selective NOP receptor agonists/antagonists are also useful tools to investigate the various mechanisms mediated by NOP receptor–N/OFQ system. As the present study, a series of (4-arylpiperidine substituted-methyl)-[bicyclic (hetero)cycloalkanobenzene] analogs was designed, synthesized, and biologically evaluated in vitro to seek and identify potent and selective, small-molecules of nonpeptide NOP receptor antagonists, which resulted in the discovery of novel potent small-molecule 15 with high human NOP receptor selectivity over human μ receptor. The structure–activity relationship (SAR) of the potency and selectivity, structure–metabolic stability relationship (SMR), and SAR of hERG (human ether-a-go-go related gene) potassium ion channel binding affinity for the analogs in the present studies in vitro provided or suggested significant and/or useful structural determinants and insights for the respective purposes. The superior profiles of compound 15 are discussed with a viewpoint of multisite interactions between ligand and NOP receptor, together with the results of previous NOP receptor agonist/antagonist studies.

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