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

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

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.
PMID: 38190615 DOI: 10.1021/acs.jmedchem.3c02148
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-HT1AR (13-15), 5-HT7R (14 and 15), and 5-HT2AR (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.

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