Recent advancements in neurobiology have sparked excitement over the potential therapeutic applications of new compounds targeting the serotonin receptor subtype 6 (5-HT6R). Researchers have developed two novel 5-HT6 receptor antagonists, PUC-10 and its indazole analogue PUC-55, which demonstrate the ability to induce autophagy through inhibition of the mammalian target of rapamycin (mTOR) pathway. This discovery may hold significant promise for improving cognitive functions and addressing neurological disorders.
The serotonin receptor 5-HT6 plays a pivotal role in neural development, influencing various processes such as neuronal migration, neurite outgrowth, and differentiation. The receptor is primarily present within limbic and cortical areas of the central nervous system, regions closely tied to memory and cognition. Dysregulation of this receptor is associated with several neurodevelopmental disorders, including schizophrenia and autism spectrum disorders.
One of the study’s lead authors, J.M. Alcaíno, noted, "Our study reports two in-house-designed 5-HT6R antagonists, PUC-10 and its indazole analogue PUC-55, which induce mTOR-dependent autophagy." The research indicates these compounds exhibit high binding affinity, with PUC-10 showing a Ki value of 14.6 nM and PUC-55 presenting 37.5 nM, making them highly effective at targeting the receptor.
Autophagy is a central cellular process for degrading damaged organelles and proteins, often linked to numerous conditions from neurodegenerative diseases to cancer. It acts as a cell’s recycling system, and the mTOR pathway serves as one of its primary regulators. Control over this pathway can promote the autophagic process, which is particularly significant for neurons.
The researchers conducted extensive cell viability tests using the human neuroblastoma SH-SY5Y cell line. Results indicated over 90% viability even at higher concentrations—demonstrated at 25 µM—for both PUC-10 and PUC-55. Importantly, both compounds showed no cytotoxicity, which makes them promising candidates for future therapeutic application.
Characterizing the mechanism of action for these antagonists revealed their capacity to induce autophagy through the mTOR signaling pathway. The compounds led to increased expression of the 5-HT6 receptor and elevation of autophagic markers within treated cells. Alcaíno added, "Both compounds induced overexpression of the 5-HT6 receptor after 24 h of stimulation, contrasting with the effects observed with Rapamycin, which is known for mTOR inhibition." This aligns with the current paradigm of exploiting autophagy to ameliorate cognitive function.
Experimentation showed significant increases in total LC3-II levels—essential for autophagy—among the treated groups when compared to the control, demonstrating the efficacy of PUC-10 and PUC-55. The ability of these compounds to engage such pathways is part of their appeal for future medication aimed at managing cognitive dysfunction.
The findings from this study, published on March 11, 2025, contribute substantially to the growing body of research connecting 5-HT6 receptors with cognitive effects. Other studies have similarly looked at the neurophysiological impacts of serotonin receptors, adding to the rationale for using 5-HT6R as therapeutic targets. Not only do these receptors present low peripheral side effects, but targeting them also shows potential for aiding cognitive performance and mood regulation.
The research team has utilized shape and electrostatic similarity searching methods within their compound library, producing promising compounds like PUC-55 with structural modifications aimed at enhancing the efficacy of 5-HT6 receptor antagonism.
Alcaíno concluded, "Both PUC-10 and PUC-55 are potential 5-HT6 receptor antagonists containing arylsulfonyl structural moieties without inducing toxicity, even at high concentrations." The study's results point to future development possibilities around compounds targeting the 5-HT6 receptor neurotransmission system.
Overall, the introduction of PUC-10 and PUC-55 opens new avenues for pharmacological applications concerning neurological health, particularly pertaining to mTOR-dependent autophagy induction, which could lead to effective treatments for neurodevelopmental disorders characterized by cognitive deficits.