TOPIC

Dual 5-HT6/SERT ligands for mitigating neuropsychiatric symptoms of dementia exerting neuroprotection against amyloid-β toxicity, memory preservation, and antidepressant-like properties

Journal

European Journal of Medicinal Chemistry

Author(s)

Agata Siwek, Monika Marcinkowska, Monika Głuch-Lutwin, Barbara Mordyl, Małgorzata Wolak, Magdalena Jastrzębska-Więsek, Natalia Wilczyńska-Zawal, Elżbieta Wyska, Katarzyna Szafrańska, Tadeusz Karcz, Olga Ostrowska, Adam Bucki, Marcin Kołaczkowski

Year

2024

In light of the biological targets alterations in dementia patients suffering from neuropsychiatric symptoms, particularly in the 5-HT6 receptor and SERT transporters, this study aimed to develop dual-acting molecules targeting both these targets. By combining a 5-substituted indole with piperazine scaffolds, we synthesized molecules with nanomolar affinities for these sites, avoiding interaction with off-targets detrimental to dementia patients. Preliminary pharmacodynamic and ADMET assays let the identification of compound 15 as a lead molecule. In vitro studies showed that 15 provided neuroprotection against Aβ toxicity and reduced the levels of proapoptotic enzymes: caspase 3 and 7. In vivo, 15 reversed MK-801-induced memory deficits and exhibited antidepressant-like effects. Further studies showed that acute administration of compound 15 at a dose of 5 mg/kg increased BDNF levels, which are crucial for supporting neuronal survival and potentially slowing cognitive decline in dementia. These findings suggest 15’s potential as a therapeutic for behavioral and psychological symptoms of dementia (BPSD), warranting further investigation.

Keywords: Q2 2024

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