Characterization of BU09059

A novel potent selective κ-receptor antagonist

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

Research output: Contribution to journalArticle

11 Citations (Scopus)
102 Downloads (Pure)

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 signalling 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, whilst 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 δreceptors, 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)177-184
Number of pages8
JournalACS Chemical Neuroscience
Volume5
Issue number3
Early online date10 Jan 2014
DOIs
Publication statusPublished - 19 Mar 2014

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kappa Opioid Receptor
Pharmacodynamics
Narcotic Antagonists
Opioid Receptors
Psychiatry
BU09059
Tissue
Derivatives
Pharmaceutical Preparations

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Casal-Dominguez, J. J., Furkert, D., Ostovar, M., Teintang, L., Clarke, M. J., Traynor, J. R., ... Bailey, S. J. (2014). Characterization of BU09059: A novel potent selective κ-receptor antagonist. ACS Chemical Neuroscience, 5(3), 177-184. https://doi.org/10.1021/cn4001507

Characterization of BU09059 : A novel potent selective κ-receptor antagonist. / Casal-Dominguez, Joseph J; Furkert, Daniel; Ostovar, Mehrnoosh; Teintang, Linnea; Clarke, Mary J; Traynor, John R; Husbands, Stephen M; Bailey, Sarah J.

In: ACS Chemical Neuroscience, Vol. 5, No. 3, 19.03.2014, p. 177-184.

Research output: Contribution to journalArticle

Casal-Dominguez, JJ, Furkert, D, Ostovar, M, Teintang, L, Clarke, MJ, Traynor, JR, Husbands, SM & Bailey, SJ 2014, 'Characterization of BU09059: A novel potent selective κ-receptor antagonist', ACS Chemical Neuroscience, vol. 5, no. 3, pp. 177-184. https://doi.org/10.1021/cn4001507
Casal-Dominguez JJ, Furkert D, Ostovar M, Teintang L, Clarke MJ, Traynor JR et al. Characterization of BU09059: A novel potent selective κ-receptor antagonist. ACS Chemical Neuroscience. 2014 Mar 19;5(3):177-184. https://doi.org/10.1021/cn4001507
Casal-Dominguez, Joseph J ; Furkert, Daniel ; Ostovar, Mehrnoosh ; Teintang, Linnea ; Clarke, Mary J ; Traynor, John R ; Husbands, Stephen M ; Bailey, Sarah J. / Characterization of BU09059 : A novel potent selective κ-receptor antagonist. In: ACS Chemical Neuroscience. 2014 ; Vol. 5, No. 3. pp. 177-184.
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