Characterization of BU09059: a novel potent selective κ-receptor antagonist

Joseph J Casal-Dominguez, Daniel Furkert, Mehrnoosh Ostovar, Linnea Teintang, Mary J Clark, John R Traynor, Stephen M Husbands, Sarah J Bailey

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)177-84
Number of pages8
JournalACS chemical neuroscience
Issue number3
Publication statusPublished - 19 Mar 2014


  • Animals
  • CHO Cells
  • Cell Line, Tumor
  • Cricetulus
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/metabolism
  • Enkephalin, D-Penicillamine (2,5)-/metabolism
  • Guanidines/metabolism
  • Guinea Pigs
  • Humans
  • Ileum/drug effects
  • In Vitro Techniques
  • Isoquinolines/chemical synthesis
  • Male
  • Mice
  • Mice, Inbred Strains
  • Molecular Structure
  • Morphinans/metabolism
  • Naltrexone/analogs & derivatives
  • Narcotic Antagonists/chemical synthesis
  • Nociception/drug effects
  • Piperidines/chemical synthesis
  • Rats
  • Receptors, Opioid, delta/antagonists & inhibitors
  • Receptors, Opioid, kappa/antagonists & inhibitors
  • Receptors, Opioid, mu/antagonists & inhibitors
  • Tetrahydroisoquinolines/chemistry
  • Vas Deferens/drug effects


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