2. Academic Validation
  3. Novel 5-HT6R modulators as mTOR-dependent neuronal autophagy inductors

Novel 5-HT6R modulators as mTOR-dependent neuronal autophagy inductors

  • Sci Rep. 2025 Mar 11;15(1):8380. doi: 10.1038/s41598-025-92755-6.
José Miguel Alcaíno # 1,  Gonzalo Vera # 2,  Gonzalo Almarza 1,  Carlos F Lagos 3 4,  Claudio A Terraza 5,  Andrea Del Campo 6,  Gonzalo Recabarren-Gajardo 7 8
Affiliations

Affiliations

  • 1 Laboratorio de Fisiología y Bioenergética Celular, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago, 7810000, Chile.
  • 2 Bioactive Heterocycles Synthesis Laboratory (BHSL), Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Avenida Vicuña Mackenna, Macul, Santiago, 4860, 7820436, Chile.
  • 3 Chemical Biology & Drug Discovery Lab, Escuela de Química y Farmacia, Facultad de Medicina y Ciencia, Universidad San Sebastián, Campus Los Leones, Providencia, Lota, Santiago, 2465, 7510157, Chile.
  • 4 Centro Ciencia & Vida, Fundación Ciencia & Vida, Av. del Valle Norte 725, Huechuraba, Santiago, 8580702, Chile.
  • 5 Research Laboratory for Organic Polymers (RLOP), Faculty of Chemistry and of Pharmacy, Pontificia Universidad Católica de Chile, Post 22, P.O. Box. 306, Santiago, Chile.
  • 6 Laboratorio de Fisiología y Bioenergética Celular, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Santiago, 7810000, Chile. andrea.delcampo@uc.cl.
  • 7 Bioactive Heterocycles Synthesis Laboratory (BHSL), Departamento de Farmacia, Facultad de Química y de Farmacia, Pontificia Universidad Católica de Chile, Avenida Vicuña Mackenna, Macul, Santiago, 4860, 7820436, Chile. grecabarren@uc.cl.
  • 8 Centro Interdisciplinario de Neurociencias, Pontificia Universidad Católica de Chile, Marcoleta 391, Santiago, 8330024, Chile. grecabarren@uc.cl.
  • # Contributed equally.
PMID: 40069248 DOI: 10.1038/s41598-025-92755-6
Abstract

Autophagy 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 (Ki = 14.6 nM) and antagonist potency (IC50 = 32 nM), demonstrated more than 90% at 25 µM cellular viability and a high capacity to induce Autophagy in the neuroblastoma SH-SY5Y cell line. Similarly, its indazole analogue, PUC-55 (Ki = 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.

Keywords

5-HT6R; Autophagy; Modulators; mTOR.

Figures
Products