title: Characterization of BU09059: a novel potent selective κ-receptor antagonist.
abstract: Kappa-opioid receptor (κ) antagonists are potential therapeutic agents for a range of psychiatric disorders. The feasibility of developing κ-antagonists has been limited by the pharmacodynamic properties of prototypic κ-selective antagonists; that is, they inhibit receptor signaling for weeks after a single administration. To address this issue, novel trans-(3R,4R)-dimethyl-4-(3-hydroxyphenyl) piperidine derivatives, based on JDTic, were designed using soft-drug principles. The aim was to determine if the phenylpiperidine-based series of κ-antagonists was amenable to incorporation of a potentially metabolically labile group, while retaining good affinity and selectivity for the κ-receptor. Opioid receptor binding affinity and selectivity of three novel compounds (BU09057, BU09058, and BU09059) were tested. BU09059, which most closely resembles JDTic, had nanomolar affinity for the κ-receptor, with 15-fold and 616-fold selectivity over μ- and δ-receptors, respectively. In isolated tissues, BU09059 was a potent and selective κ-antagonist (pA2 8.62) compared with BU09057 (pA2 6.87) and BU09058 (pA2 6.76) which were not κ-selective. In vivo, BU09059 (3 and 10 mg/kg) significantly blocked U50,488-induced antinociception and was as potent as, but shorter acting than, the prototypic selective κ-antagonist norBNI. These data show that a new JDTic analogue, BU09059, retains high affinity and selectivity for the κ-receptor and has a shorter duration of κ-antagonist action in vivo.
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath , Bath BA2 7AY, United Kingdom.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Casal-Dominguez
authors.forename: Daniel
authors.initials: D
authors.lastname: Furkert
authors.forename: Mehrnoosh
authors.initials: M
authors.lastname: Ostovar
authors.forename: Linnea
authors.initials: L
authors.lastname: Teintang
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Clark
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Husbands
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Bailey
mesh_terms: D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D003412:Cricetulus; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000378:metabolism; D006146:Guanidines / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D009019:Morphinans / Q000378:metabolism; D009271:Naltrexone / Q000031:analogs & derivatives / Q000378:metabolism; D009292:Narcotic Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D059225:Nociception / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects
chemical_list: C411465:17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5'-guanidinyl-3,14-dihydroxyindolo(2',3'-6,7)morphinan; C433814:7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide; C000593254:BU09059; D006146:Guanidines; D007546:Isoquinolines; D009019:Morphinans; D009292:Narcotic Antagonists; D010880:Piperidines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C051844:norbinaltorphimine; D009271:Naltrexone; D020881:Enkephalin, D-Penicillamine (2,5)-