Side Groups Convert the α7 Nicotinic Receptor Agonist Ether Quinuclidine into a Type I Positive Allosteric Modulator

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dc.contributor.authorViscarra, Franco
dc.contributor.authorChrestia, Juan Facundo
dc.contributor.authorSanchez, Yaima
dc.contributor.authorPerez, Edwin G.
dc.contributor.authorBiggin, Philip C.
dc.contributor.authorBouzat, Cecilia
dc.contributor.authorBermudez, Isabel
dc.contributor.authorLopez, Jhon J.
dc.date.accessioned2025-01-20T20:08:14Z
dc.date.available2025-01-20T20:08:14Z
dc.date.issued2023
dc.description.abstractThe quinuclidine scaffold has been extensively used forthe developmentof nicotinic acetylcholine receptor (nAChR) agonists, with hydrophobicsubstituents at position 3 of the quinuclidine framework providingselectivity for & alpha;7 nAChRs. In this study, six new ligands (4-9) containing a 3-(pyridin-3-yloxy)quinuclidinemoiety (ether quinuclidine) were synthesized to gain a better understandingof the structural-functional properties of ether quinuclidines.To evaluate the pharmacological activity of these ligands, two-electrodevoltage-clamp and single-channel recordings were performed. Only ligand 4 activated & alpha;7 nAChR. Ligands 5 and 7 had no effects on & alpha;7 nAChR, but ligands 6, 8, and 9 potentiated the currents evokedby ACh. Ligand 6 was the most potent and efficaciousof the potentiating ligands, with an estimated EC50 forpotentiation of 12.6 & PLUSMN; 3.32 & mu;M and a maximal potentiationof EC20 ACh responses of 850 & PLUSMN; 120%. Ligand 6 increased the maximal ACh responses without changing thekinetics of the current responses. At the single-channel level, thepotentiation exerted by ligand 6 was evidenced in thelow micromolar concentration range by the appearance of prolongedbursts of channel openings. Furthermore, computational studies revealedthe preference of ligand 6 for an intersubunit site inthe transmembrane domain and highlighted some putative key interactionsthat explain the different profiles of the synthesized ligands. Notably,Met276 in the 15 & PRIME; position of the transmembrane domain 2 almostabolished the effects of ligand 6 when mutated to Leu.We conclude that ligand 6 is a novel type I positiveallosteric modulator (PAM-I) of & alpha;7 nAChR.
dc.fuente.origenWOS
dc.identifier.doi10.1021/acschemneuro.3c00225
dc.identifier.issn1948-7193
dc.identifier.urihttps://doi.org/10.1021/acschemneuro.3c00225
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/91884
dc.identifier.wosidWOS:001040388500001
dc.issue.numero16
dc.language.isoen
dc.pagina.final2887
dc.pagina.inicio2876
dc.revistaAcs chemical neuroscience
dc.rightsacceso restringido
dc.subjectEther quinuclidines
dc.subjectchemical synthesis
dc.subjectpositiveallosteric modulator
dc.subjectvoltage-clamp
dc.subjectsingle-channelrecordings
dc.subjectmolecular docking
dc.subjectmolecular dynamics
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleSide Groups Convert the α7 Nicotinic Receptor Agonist Ether Quinuclidine into a Type I Positive Allosteric Modulator
dc.typeartículo
dc.volumen14
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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