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dc.contributor.authorZhou, Lei
dc.contributor.authorStahl, Edward L.
dc.contributor.authorLovell, Kimberly M.
dc.contributor.authorFrankowski, Kevin J.
dc.contributor.authorPrisinzano, Thomas E.
dc.contributor.authorAubé, Jeffrey
dc.contributor.authorBohn, Laura M.
dc.date.accessioned2017-02-15T19:32:21Z
dc.date.available2017-02-15T19:32:21Z
dc.date.issued2015-12
dc.identifier.citationZhou, L., Stahl, E. L., Lovell, K. M., Frankowski, K. J., Prisinzano, T. E., Aubé, J., & Bohn, L. M. (2015). Characterization of kappa opioid receptor mediated, dynorphin-stimulated [35S]GTPγS binding in mouse striatum for the evaluation of selective KOR ligands in an endogenous setting. Neuropharmacology, 99, 131–141. http://doi.org/10.1016/j.neuropharm.2015.07.001en_US
dc.identifier.urihttp://hdl.handle.net/1808/23182
dc.description.abstractDifferential modulation of kappa opioid receptor (KOR) signaling has been a proposed strategy for developing therapies for drug addiction and depression by either activating or blocking this receptor. Hence, there have been significant efforts to generate ligands with diverse pharmacological properties including partial agonists, antagonists, allosteric modulators as well as ligands that selectively activate some pathways while not engaging others (biased agonists). It is becoming increasingly evident that G protein coupled receptor signaling events are context dependent and that what may occur in cell based assays may not be fully indicative of signaling events that occur in the naturally occurring environment. As new ligands are developed, it is important to assess their signaling capacity in relevant endogenous systems in comparison to the performance of endogenous agonists. Since KOR is considered the cognate receptor for dynorphin peptides we have evaluated the selectivity profiles of dynorphin peptides in wild-type (WT), KOR knockout (KOR-KO), and mu opioid receptor knockout (MOR-KO) mice using [35S]GTPγS binding assay in striatal membrane preparations. We find that while the small molecule KOR agonist U69,593, is very selective for KOR, dynorphin peptides promiscuously stimulate G protein signaling in striatum. Furthermore, our studies demonstrate that norBNI and 5′GNTI are highly nonselective antagonists as they maintain full potency and efficacy against dynorphin signaling in the absence of KOR. Characterization of a new KOR antagonist, which may be more selective than NorBNI and 5′GNTI, is presented using this approach.en_US
dc.publisherElsevieren_US
dc.rightsThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectDynorphinen_US
dc.subjectKappa opioid receptoren_US
dc.subject[35S]GTPγS bindingen_US
dc.subjectMouse striatumen_US
dc.subjectSelectivityen_US
dc.subjectDrug discoveryen_US
dc.subjectKOR antagonisten_US
dc.titleCharacterization of kappa opioid receptor mediated, dynorphin-stimulated [35S]GTPγS binding in mouse striatum for the evaluation of selective KOR ligands in an endogenous settingen_US
dc.typeArticleen_US
kusw.kuauthorFrankowski, Kevin J.
kusw.kuauthorPrisinzano, Thomas E.
kusw.kuauthorAubé, Jeffrey
kusw.kudepartmentMedicinal Chemistryen_US
kusw.oanotesPer SHERPA/RoMEO 2/15/2016: Author's Pre-print: green tick author can archive pre-print (ie pre-refereeing) Author's Post-print: green tick author can archive post-print (ie final draft post-refereeing) Publisher's Version/PDF: cross author cannot archive publisher's version/PDF General Conditions:

Authors pre-print on any website, including arXiv and RePEC Author's post-print on author's personal website immediately Author's post-print on open access repository after an embargo period of between 12 months and 48 months Permitted deposit due to Funding Body, Institutional and Governmental policy or mandate, may be required to comply with embargo periods of 12 months to 48 months Author's post-print may be used to update arXiv and RepEC Publisher's version/PDF cannot be used Must link to publisher version with DOI Author's post-print must be released with a Creative Commons Attribution Non-Commercial No Derivatives License
en_US
dc.identifier.doi10.1016/j.neuropharm.2015.07.001en_US
dc.identifier.orcidhttps://orcid.org/0000-0003-1049-5767
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.rights.accessrightsopenAccess


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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Except where otherwise noted, this item's license is described as: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.