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dc.contributor.author
Arias, Hugo Rubén
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dc.contributor.author
Feuerbach, Dominik
dc.contributor.author
Ortells, Marcelo Oscar
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dc.date.available
2018-05-29T21:38:09Z
dc.date.issued
2016-09
dc.identifier.citation
Arias, Hugo Rubén; Feuerbach, Dominik; Ortells, Marcelo Oscar; Bupropion and its photoreactive analog (±)-SADU-3-72 interact with luminal and non-luminal sites at human α4β2 nicotinic acetylcholine receptors; Pergamon-Elsevier Science Ltd; Neurochemistry International; 100; 9-2016; 67-77
dc.identifier.issn
0197-0186
dc.identifier.uri
http://hdl.handle.net/11336/46551
dc.description.abstract
The interaction of (±)-bupropion [(±)-BP] with the human (h) α4β2 nicotinic acetylcholine receptor (AChR) was compared to that for its photoreactive analog (±)-2-(N-tert-butylamino)-3′-iodo-4′-azidopropiophenone [(±)-SADU-3-72]. Ca2+ influx results indicated that (±)-SADU-3-72 and (±)-BP inhibit hα4β2 AChRs with practically the same potency. However, (±)-SADU-3-72 binds to the [3H]imipramine sites at resting and desensitized hα4β2 AChRs with 3-fold higher affinity compared to that for (±)-BP, which is supported by molecular docking results. The docking results also indicate that each isomer of BP and SADU-3-72, in the protonated state, interacts with luminal and non-luminal sites. In the channel lumen, both ligands bind to two overlapping subsites, one that overlaps the imipramine site, and another much closer to the cytoplasmic side. The results suggest, for the first time, three differentiated non-luminal domains, including the transmembrane (TMD), extracellular (ECD), and ECD-TMD junction. In the ECD-TMD junction, BP and SADU-3-72 bind to overlapping sites. Interestingly, only SADU-3-72 binds to intrasubunit and intersubunit sites in the TMD, and to additional sites in the ECD. Our results are consistent with a model where BP and SADU-3-72 bind to overlapping sites in the luminal and ECD-TMD junctional domains of the hα4β2, whereas only SADU-3-72 binds to additional non-luminal sites. The BP junctional site opens the door for additional inhibitory mechanisms. The pharmacological properties of (±)-SADU-3-72 showed in this work support further photolabeling studies to mapping the BP binding sites in the hα4β2 AChR.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Pergamon-Elsevier Science Ltd
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.subject
Human Α4β2 Nicotinic Acetylcholine Receptor
dc.subject
Bupropion
dc.subject
(±)-Sadu-3-72
dc.subject
Molecular Docking
dc.subject.classification
Otras Ciencias Biológicas
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Bupropion and its photoreactive analog (±)-SADU-3-72 interact with luminal and non-luminal sites at human α4β2 nicotinic acetylcholine receptors
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-05-29T18:34:52Z
dc.journal.volume
100
dc.journal.pagination
67-77
dc.journal.pais
Estados Unidos
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dc.description.fil
Fil: Arias, Hugo Rubén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. California Northstate University College of Medicine; Estados Unidos
dc.description.fil
Fil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research; Suiza
dc.description.fil
Fil: Ortells, Marcelo Oscar. Universidad de Morón. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.journal.title
Neurochemistry International
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.neuint.2016.08.013
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0197018616300791
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