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Selective κ opioid antagonists nor-BNI, GNTI and JDTic have low affinities for non-opioid receptors and transporters

Munro, Thomas A, Huang, Xi-Ping, Inglese, Carmela, Perrone, Maria Grazia, Van't Veer, Ashlee, Carroll, F. Ivy, Béguin, Cécile, Carlezon, William A, Colabufo, Nicola A, Cohen, Bruce M and Roth, Bryan L 2013, Selective κ opioid antagonists nor-BNI, GNTI and JDTic have low affinities for non-opioid receptors and transporters, PloS one, vol. 8, no. 8, pp. 1-9, doi: 10.1371/journal.pone.0070701.

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Title Selective κ opioid antagonists nor-BNI, GNTI and JDTic have low affinities for non-opioid receptors and transporters
Author(s) Munro, Thomas AORCID iD for Munro, Thomas A orcid.org/0000-0002-3366-7149
Huang, Xi-Ping
Inglese, Carmela
Perrone, Maria Grazia
Van't Veer, Ashlee
Carroll, F. Ivy
Béguin, Cécile
Carlezon, William A
Colabufo, Nicola A
Cohen, Bruce M
Roth, Bryan L
Journal name PloS one
Volume number 8
Issue number 8
Start page 1
End page 9
Total pages 9
Publisher Public Library of Science
Place of publication San Francisco, Calif.
Publication date 2013-08
ISSN 1932-6203
Keyword(s) Allosteric Regulation
Biological Transport
Caco-2 Cells
Calcium
Guanidines
Humans
Kinetics
Morphinans
Naltrexone
Narcotic Antagonists
Norepinephrine
Norepinephrine Plasma Membrane Transport Proteins
Piperidines
Protein Binding
Receptors, Adrenergic, alpha
Receptors, Opioid, delta
Receptors, Opioid, kappa
Receptors, Opioid, mu
Tetrahydroisoquinolines
Summary
Background
Nor-BNI, GNTI and JDTic induce selective κ opioid antagonism that is delayed and extremely prolonged, but some other effects are of rapid onset and brief duration. The transient effects of these compounds differ, suggesting that some of them may be mediated by other targets.

Results

In binding assays, the three antagonists showed no detectable affinity (Ki≥10 µM) for most non-opioid receptors and transporters (26 of 43 tested). There was no non-opioid target for which all three compounds shared detectable affinity, or for which any two shared sub-micromolar affinity. All three compounds showed low nanomolar affinity for κ opioid receptors, with moderate selectivity over μ and δ (3 to 44-fold). Nor-BNI bound weakly to the α2C-adrenoceptor (Ki = 630 nM). GNTI enhanced calcium mobilization by noradrenaline at the α1A-adrenoceptor (EC50 = 41 nM), but did not activate the receptor, displace radioligands, or enhance PI hydrolysis. This suggests that it is a functionally-selective allosteric enhancer. GNTI was also a weak M1 receptor antagonist (KB = 3.7 µM). JDTic bound to the noradrenaline transporter (Ki = 54 nM), but only weakly inhibited transport (IC50 = 1.1 µM). JDTic also bound to the opioid-like receptor NOP (Ki = 12 nM), but gave little antagonism even at 30 µM. All three compounds exhibited rapid permeation and active efflux across Caco-2 cell monolayers.

Conclusions

Across 43 non-opioid CNS targets, only GNTI exhibited a potent functional effect (allosteric enhancement of α1A-adrenoceptors). This may contribute to GNTI's severe transient effects. Plasma concentrations of nor-BNI and GNTI may be high enough to affect some peripheral non-opioid targets. Nonetheless, κ opioid antagonism persists for weeks or months after these transient effects dissipate. With an adequate pre-administration interval, our results therefore strengthen the evidence that nor-BNI, GNTI and JDTic are highly selective κ opioid antagonists.


Language eng
DOI 10.1371/journal.pone.0070701
Field of Research MD Multidisciplinary
Socio Economic Objective 0 Not Applicable
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2013, Munro et al.
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30093502

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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.