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dc.contributor.author
Tae, Han Shen
dc.contributor.author
Ortells, Marcelo Oscar
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dc.contributor.author
Yousuf, Arsalan
dc.contributor.author
Xu, Sophia Q.
dc.contributor.author
Akk, Gustav
dc.contributor.author
Adams, David J.
dc.contributor.author
Arias, Hugo Rubén
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dc.date.available
2024-05-03T13:33:45Z
dc.date.issued
2024-04
dc.identifier.citation
Tae, Han Shen; Ortells, Marcelo Oscar; Yousuf, Arsalan; Xu, Sophia Q.; Akk, Gustav; et al.; Tabernanthalog and ibogainalog inhibit the α7 and α9α10 nicotinic acetylcholine receptors via different mechanisms and with higher potency than the GABAA receptor and CaV2.2 channel; Pergamon-Elsevier Science Ltd; Biochemical Pharmacology; 223; 4-2024; 1-14
dc.identifier.issn
0006-2952
dc.identifier.uri
http://hdl.handle.net/11336/234463
dc.description.abstract
In this study, we have investigated the pharmacological activity and structural interaction of two novel psychoplastogens, tabernanthalog (TBG) and ibogainalog (IBG) at heterologously-expressed rat (r) and human (h) nicotinic acetylcholine receptors (nAChRs), the rα1β2γ2L γ-aminobutyric acid type A receptor (GABAAR), and the human voltage-gated N-type calcium channel (CaV2.2 channel). Both compounds inhibited the nAChRs with the following receptor selectivity: α9α10 > α7 > α3β2 ≅ α3β4, indicating that β2/β4 subunits are relatively less important for their activity. The potencies of TBG and IBG were comparable at hα7 and hα9α10 subtypes, and comparable to their rat counterparts. TBG- and IBG-induced inhibition of rα7 was ACh concentration-independent and voltage-dependent, whereas rα9α10 inhibition was ACh concentration-dependent and voltage-independent, suggesting that they interact with the α7 ion channel pore and α9α10 orthosteric ligand binding site, respectively. These results were supported by molecular docking studies showing that at the α7 model TBG forms stable interactions with luminal rings at 9′, 13′, and 16′, whereas IBG mostly interacts with the extracellular-transmembrane junction. In the α9α10 model, however, these compounds interacted with several residues from the principal (+) and complementary (–) sides in the transmitter binding site. Ibogaminalog (DM506) also interacted with a non-luminal site at α7, and one α9α10 orthosteric site. TBG and IBG inhibited the GABAAR and CaV2.2 channels with 10 to 30-fold lower potencies. In sum, we show that TBG and IBG inhibit the α7 and α9α10 nAChRs by noncompetitive and competitive mechanisms, respectively, and with higher potency than the GABAAR and CaV2.2 channel.
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/2.5/ar/
dc.subject
Psychoplastogens
dc.subject
Tabernanthalog
dc.subject
Ibogainalog
dc.subject
Nicotinic receptors
dc.subject
GABAA receptor
dc.subject
CaV2.2 channel
dc.subject.classification
Bioquímica y Biología Molecular
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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
Tabernanthalog and ibogainalog inhibit the α7 and α9α10 nicotinic acetylcholine receptors via different mechanisms and with higher potency than the GABAA receptor and CaV2.2 channel
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2024-04-26T11:59:25Z
dc.journal.volume
223
dc.journal.pagination
1-14
dc.journal.pais
Estados Unidos
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dc.description.fil
Fil: Tae, Han Shen. University Of Wollongong; Australia
dc.description.fil
Fil: Ortells, Marcelo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Morón; Argentina
dc.description.fil
Fil: Yousuf, Arsalan. University Of Wollongong; Australia
dc.description.fil
Fil: Xu, Sophia Q.. Washington University in St. Louis; Estados Unidos
dc.description.fil
Fil: Akk, Gustav. Washington University in St. Louis; Estados Unidos
dc.description.fil
Fil: Adams, David J.. University Of Wollongong; Australia
dc.description.fil
Fil: Arias, Hugo Rubén. Oklahoma State University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.journal.title
Biochemical Pharmacology
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0006295224001667
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.bcp.2024.116183
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