Novel 5-HT<sub>6</sub>R modulators as mTOR-dependent neuronal autophagy inductors

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dc.article.number8380
dc.contributor.authorAlcaino Vergara, Jose Miguel
dc.contributor.authorVera, Gonzalo
dc.contributor.authorAlmarza, Gonzalo
dc.contributor.authorLagos, Carlos F.
dc.contributor.authorTerraza Inostroza, Claudio
dc.contributor.authorDel Campo Sfeir, Andrea
dc.contributor.authorRecabarren-Gajardo, Gonzalo
dc.date.accessioned2025-05-01T10:31:07Z
dc.date.available2025-05-01T10:31:07Z
dc.date.issued2025
dc.description.abstractAutophagy is a natural process in which the cell degrades substances through the lysosomal pathway. One of the most studied mechanisms for regulating autophagy is the mTOR signaling pathway. Recent research has shown that the 5-HT6 receptor is linked to the mTOR pathway and can affect cognition in various neurodevelopmental models. Therefore, developing 5-HT6 receptor antagonists could improve cognition by inducing autophagy through the inhibition of the mTOR pathway. Our study reports two in-house-designed 5-HT6R antagonists, PUC-10 and its indazole analogue PUC-55, that induce mTOR-dependent autophagy. PUC-10, an indole-based 5-HT6 receptor antagonist with high binding affinity (K-i = 14.6 nM) and antagonist potency (IC50 = 32 nM), demonstrated more than 90% at 25 mu M cellular viability and a high capacity to induce autophagy in the neuroblastoma SH-SY5Y cell line. Similarly, its indazole analogue, PUC-55 (K-i = 37.5 nM), exhibited high cellular viability and potent autophagy-inducing activity. Both compounds induced overexpression of the 5-HT6 receptor after 24 h of stimulation, contrasting with the effects observed with Rapamycin (100 nM), a well-known mTOR inhibitor. Additionally, the signaling pathway was characterized, showing that both PUC-10 and PUC-55 induce autophagy by inhibiting the mTOR pathway, suggesting their potential therapeutic applications for neurological disorders.
dc.description.funderInstituto Milenio para la Investigacion del Cuidado
dc.format.extent13 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1038/s41598-025-92755-6
dc.identifier.eisbn978-1-5106-5352-8
dc.identifier.eissn2045-2322
dc.identifier.eissn2045-2322
dc.identifier.isbn978-1-5106-5351-1
dc.identifier.issn0277-786X
dc.identifier.pubmedid35994695
dc.identifier.scieloidS0718-69242020000300109
dc.identifier.scopusidSCOPUS_ID:86000526698
dc.identifier.urihttps://doi.org/10.1038/s41598-025-92755-6
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/103713
dc.identifier.wosidWOS:001442602500030
dc.information.autorucEscuela de Química; Alcaino Vergara, Jose Miguel; S/I; 1066497
dc.information.autorucEscuela de Química; Terraza Inostroza, Claudio; 0000-0002-6326-8771; 1001668
dc.information.autorucEscuela de Química; Del Campo Sfeir, Andrea; 0000-0003-3830-7334; 1099680
dc.issue.numero1
dc.language.isoen
dc.nota.accesoContenido completo
dc.pagina.final22
dc.pagina.inicio14
dc.relation.ispartofJCO global oncology
dc.revistaScientific Reports
dc.rightsacceso abierto
dc.subject5-HT6R
dc.subjectModulators
dc.subjectmTOR
dc.subjectAutophagy
dc.subject.ddc510
dc.subject.deweyMatemática física y químicaes_ES
dc.subject.ods03 Good health and well-being
dc.subject.odspa03 Salud y bienestar
dc.titleNovel 5-HT<sub>6</sub>R modulators as mTOR-dependent neuronal autophagy inductors
dc.typeartículo
dc.volumen15
sipa.codpersvinculados1066497
sipa.codpersvinculados1001668
sipa.codpersvinculados1099680
sipa.indexWOS
sipa.trazabilidadCarga WOS-SCOPUS;01-05-2025
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