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DC Field | Value | Language |
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dc.contributor.author | Ågren, Richard | - |
dc.contributor.author | Zeberg, Hugo | - |
dc.contributor.author | Stepniewski, Tomasz Maciej | - |
dc.contributor.author | Free, R. Benjamin | - |
dc.contributor.author | Reilly, Sean W. | - |
dc.contributor.author | Luedtke, Robert R. | - |
dc.contributor.author | Århem, Peter | - |
dc.contributor.author | Ciruela Alférez, Francisco | - |
dc.contributor.author | Sibley, David R. | - |
dc.contributor.author | Mach, Robert H. | - |
dc.contributor.author | Selent, Jana | - |
dc.contributor.author | Nilsson, Johanna | - |
dc.contributor.author | Sahlholm, Kristoffer | - |
dc.date.accessioned | 2021-02-05T16:58:34Z | - |
dc.date.issued | 2020-10-07 | - |
dc.identifier.issn | 1948-7193 | - |
dc.identifier.uri | http://hdl.handle.net/2445/173716 | - |
dc.description.abstract | A solid understanding of the mechanisms governing ligand binding is crucial for rational design of therapeutics targeting the dopamine D2 receptor (D2R). Here, we use G protein-coupled inward rectifier potassium (GIRK) channel activation in Xenopus oocytes to measure the kinetics of D2R antagonism by a series of aripiprazole analogues, as well as the recovery of dopamine (DA) responsivity upon washout. The aripiprazole analogues comprise an orthosteric and a secondary pharmacophore and differ by the length of the saturated carbon linker joining these two pharmacophores. Two compounds containing 3- and 5-carbon linkers allowed for a similar extent of recovery from antagonism in the presence of 1 or 100 μM DA (>25 and >90% of control, respectively), whereas recovery was less prominent (∼20%) upon washout of the 4-carbon linker compound, SV-III-130, both with 1 and 100 μM DA. Prolonging the coincubation time with SV-III-130 further diminished recovery. Curve-shift experiments were consistent with competition between SV-III-130 and DA. Two mutations in the secondary binding pocket (V91A and E95A) of D2R decreased antagonistic potency and increased recovery from SV-III-130 antagonism, whereas a third mutation (L94A) only increased recovery. Our results suggest that the secondary binding pocket influences recovery from inhibition by the studied aripiprazole analogues. We propose a mechanism, supported by in silico modeling, whereby SV-III-130 initially binds reversibly to the D2R, after which the drug-receptor complex undergoes a slow transition to a second ligand-bound state, which is dependent on secondary binding pocket integrity and irreversible during the time frame of our experiments. | - |
dc.format.extent | 14 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | American Chemical Society | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.1021/acschemneuro.0c00477 | - |
dc.relation.ispartof | Acs Chemical Neuroscience, 2020, vol. 11 , num. 19, p. 3130-3143 | - |
dc.relation.uri | https://doi.org/10.1021/acschemneuro.0c00477 | - |
dc.rights | cc-by (c) Ågren et al, 2020 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.source | Articles publicats en revistes (Patologia i Terapèutica Experimental) | - |
dc.subject.classification | Dinàmica molecular | - |
dc.subject.classification | Dopamina | - |
dc.subject.classification | Receptors cel·lulars | - |
dc.subject.other | Molecular dynamics | - |
dc.subject.other | Dopamine | - |
dc.subject.other | Cell receptors | - |
dc.title | Ligand with Two Modes of Interaction with the Dopamine D2 Receptor–An Induced-Fit Mechanism of Insurmountable Antagonism | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.identifier.idgrec | 706501 | - |
dc.date.updated | 2021-02-05T16:58:34Z | - |
dc.rights.accessRights | info:eu-repo/semantics/embargoedAccess | - |
dc.date.embargoEndDate | info:eu-repo/date/embargoEnd/2021-10-07 | - |
dc.identifier.pmid | 32865974 | - |
Appears in Collections: | Articles publicats en revistes (Patologia i Terapèutica Experimental) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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706501.pdf | 8.75 MB | Adobe PDF | View/Open |
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