title: 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.
abstract: 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.
authors.affiliation: Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., 5-2 Taketoyo, Aichi 470-2393, Japan. Electronic address: Shigeo_Hayashi@nifty.com.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., 5-2 Taketoyo, Aichi 470-2393, Japan.
authors.forename: Katsuyo
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., 5-2 Taketoyo, Aichi 470-2393, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Mihara
authors.affiliation: Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., 5-2 Taketoyo, Aichi 470-2393, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Nakata
authors.affiliation: Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., 5-2 Taketoyo, Aichi 470-2393, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Emoto
authors.affiliation: Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Japan Inc., 5-2 Taketoyo, Aichi 470-2393, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Ohta
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D006839:Hydrocarbons, Acyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
chemical_list: D006839:Hydrocarbons, Acyclic; D010880:Piperidines; D011957:Receptors, Opioid; D054852:Small Molecule Libraries; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human
keywords: HERG potassium ion channel binding; Human NOP (ORL1) receptor selective antagonist; Metabolic stability; Multisite interactions with NOP receptor; Nociceptin/Orphanin FQ (N/OFQ); Prolong QT interval issues