First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer's Disease PMID: 38190615

ADC Targets in Oncology

2026-04-10

First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer's Disease

J Med Chem. 2024 Jan 8. doi: 10.1021/acs.jmedchem.3c02148.

Patryk Pyka ¹ ² ³ , Wawrzyniec Haberek ¹ ² ³ , Małgorzata Więcek ¹ , Ewa Szymanska ¹ , Wesam Ali ¹ ² , Agnieszka Cios ⁴ , Magdalena Jastrzębska-Więsek ⁴ , Grzegorz Satała ⁵ , Sabina Podlewska ⁵ , Silvia Di Giacomo ⁶ ⁷ , Antonella Di Sotto ⁶ , Sabrina Garbo ⁸ , Tadeusz Karcz ¹ , Chiara Lambona ⁹ , Francesco Marocco ⁸ , Gniewomir Latacz ¹ , Sylwia Sudoł-Tałaj ¹ ³ , Barbara Mordyl ¹⁰ , Monika Głuch-Lutwin ¹⁰ , Agata Siwek ¹⁰ , Kinga Czarnota-Łydka ¹ ³ , Dawid Gogola ¹ ³ , Agnieszka Olejarz-Maciej ¹ , Natalia Wilczyńska-Zawal ⁴ , Ewelina Honkisz-Orzechowska ¹ , Małgorzata Starek ¹¹ , Monika Dąbrowska ¹¹ , Katarzyna Kucwaj-Brysz ¹ , Rossella Fioravanti ⁹ , Muhammad Jawad Nasim ² , Marius Hittinger ¹² ¹³ , Anna Partyka ⁴ , Anna Wesołowska ⁴ , Cecilia Battistelli ⁸ , Clemens Zwergel ² ⁹ ¹² , Jadwiga Handzlik ¹

Affiliations

1. Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
2. Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, Campus B 2.1, D-66123 Saarbrücken, Germany.
3. Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, św. Łazarza 15, 31-530 Kraków, Poland.
4. Department of Clinical Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
5. Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
6. Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
7. Italian National Institute of Health (ISS), Viale Regina Elena 299, 00161 Rome, Italy.
8. Department of Molecular Medicine, Istituto Pasteur Italia, Fondazione Cenci-Bolognetti, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
9. Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
10. Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
11. Department of Inorganic and Analytical Chemistry, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.
12. Department of Drug Discovery, Pharmbiotec gGmbH, Nußkopf 39, 66578 Schiffweiler, Germany.
13. Department of Drug Delivery, Pharmbiotec gGmbH, Nußkopf 39, 66578 Schiffweiler, Germany.

Abstract

Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT₆ emerged as a promising target for AD treatment; thus, here a new series of 5-HT₆R ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HT₆R affinity and selectivity over 5-HT_1AR (13-15), 5-HT₇R (14 and 15), and 5-HT_2AR (13). Compound 15 displayed high selectivity for 5-HT₆R over Other central nervous system receptors and exhibited low risk of cardio-, hepato-, and nephrotoxicity and no mutagenicity, indicating its "drug-like" potential. Compound 15 also demonstrated neuroprotection against rotenone-induced neurotoxicity as well as antioxidant and Glutathione Peroxidase (GPx)-like activity and regulated antioxidant and pro-inflammatory genes and NRF2 nuclear translocation. In rats, 15 showed satisfying pharmacokinetics, penetrated the blood-brain barrier, reversed MK-801-induced memory impairment, and exhibited anxiolytic-like properties. 15's neuroprotective and procognitive-like effects, stronger than those of the approved drug donepezil, may pave the way for the use of selenotriazines to inhibit both causes and symptoms in AD therapy.