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dc.contributor.author
Viscarra, Franco  
dc.contributor.author
Chrestia, Juan Facundo  
dc.contributor.author
Sanchez, Yaima  
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Pérez, Edwin G.  
dc.contributor.author
Biggin, Philip C.  
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Bouzat, Cecilia Beatriz  
dc.contributor.author
Bermudez, Isabel  
dc.contributor.author
López, Jhon J.  
dc.date.available
2024-01-18T15:01:48Z  
dc.date.issued
2023-08-16  
dc.identifier.citation
Viscarra, Franco; Chrestia, Juan Facundo; Sanchez, Yaima; Pérez, Edwin G.; Biggin, Philip C.; et al.; Side Groups Convert the α7 Nicotinic Receptor Agonist Ether Quinuclidine into a Type I Positive Allosteric Modulator; American Chemical Society; ACS Chemical Neuroscience; 14; 16; 16-8-2023; 2876-2887  
dc.identifier.issn
1948-7193  
dc.identifier.uri
http://hdl.handle.net/11336/224141  
dc.description.abstract
The quinuclidine scaffold has been extensively used for the development of nicotinic acetylcholine receptor (nAChR) agonists, with hydrophobic substituents at position 3 of the quinuclidine framework providing selectivity for α7 nAChRs. In this study, six new ligands (4-9) containing a 3-(pyridin-3-yloxy)quinuclidine moiety (ether quinuclidine) were synthesized to gain a better understanding of the structural-functional properties of ether quinuclidines. To evaluate the pharmacological activity of these ligands, two-electrode voltage-clamp and single-channel recordings were performed. Only ligand 4 activated α7 nAChR. Ligands 5 and 7 had no effects on α7 nAChR, but ligands 6, 8, and 9 potentiated the currents evoked by ACh. Ligand 6 was the most potent and efficacious of the potentiating ligands, with an estimated EC50 for potentiation of 12.6 ± 3.32 μM and a maximal potentiation of EC20 ACh responses of 850 ± 120%. Ligand 6 increased the maximal ACh responses without changing the kinetics of the current responses. At the single-channel level, the potentiation exerted by ligand 6 was evidenced in the low micromolar concentration range by the appearance of prolonged bursts of channel openings. Furthermore, computational studies revealed the preference of ligand 6 for an intersubunit site in the transmembrane domain and highlighted some putative key interactions that explain the different profiles of the synthesized ligands. Notably, Met276 in the 15′ position of the transmembrane domain 2 almost abolished the effects of ligand 6 when mutated to Leu. We conclude that ligand 6 is a novel type I positive allosteric modulator (PAM-I) of α7 nAChR.  
dc.format
application/pdf  
dc.language.iso
eng  
dc.publisher
American Chemical Society  
dc.rights
info:eu-repo/semantics/restrictedAccess  
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/  
dc.subject
CHEMICAL SYNTHESIS  
dc.subject
ETHER QUINUCLIDINES  
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MOLECULAR DOCKING  
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MOLECULAR DYNAMICS  
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POSITIVE ALLOSTERIC MODULATOR  
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SINGLE-CHANNEL RECORDINGS  
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VOLTAGE-CLAMP  
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Biofísica  
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Ciencias Biológicas  
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CIENCIAS NATURALES Y EXACTAS  
dc.title
Side Groups Convert the α7 Nicotinic Receptor Agonist Ether Quinuclidine into a Type I Positive Allosteric Modulator  
dc.type
info:eu-repo/semantics/article  
dc.type
info:ar-repo/semantics/artículo  
dc.type
info:eu-repo/semantics/publishedVersion  
dc.date.updated
2024-01-16T14:08:05Z  
dc.journal.volume
14  
dc.journal.number
16  
dc.journal.pagination
2876-2887  
dc.journal.pais
Estados Unidos  
dc.journal.ciudad
Washington  
dc.description.fil
Fil: Viscarra, Franco. Oxford Brookes University (oxford Brookes University); . University of Oxford; Reino Unido  
dc.description.fil
Fil: Chrestia, Juan Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina  
dc.description.fil
Fil: Sanchez, Yaima. Universidad de Concepción; Chile  
dc.description.fil
Fil: Pérez, Edwin G.. Pontificia Universidad Católica de Chile; Chile  
dc.description.fil
Fil: Biggin, Philip C.. University of Oxford; Reino Unido  
dc.description.fil
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina  
dc.description.fil
Fil: Bermudez, Isabel. University of Oxford; Reino Unido  
dc.description.fil
Fil: López, Jhon J.. Universidad de Concepción; Chile  
dc.journal.title
ACS Chemical Neuroscience  
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acschemneuro.3c00225  
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1021/acschemneuro.3c00225