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Multifunctional Arylsulfone and Arylsulfonamide-Based Ligands with Prominent Mood-Modulating Activity and Benign Safety Profile, Targeting Neuropsychiatric Symptoms of Dementia.

Authors
  • Marcinkowska, Monika1
  • Bucki, Adam1
  • Sniecikowska, Joanna1
  • Zagórska, Agnieszka1
  • Fajkis-Zajączkowska, Nikola1
  • Siwek, Agata1
  • Gluch-Lutwin, Monika1
  • Żmudzki, Paweł1
  • Jastrzebska-Wiesek, Magdalena1
  • Partyka, Anna1
  • Wesołowska, Anna1
  • Abram, Michał1
  • Przejczowska-Pomierny, Katarzyna1
  • Cios, Agnieszka1
  • Wyska, Elżbieta1
  • Mika, Kamil1
  • Kotańska, Magdalena1
  • Mierzejewski, Paweł2
  • Kolaczkowski, Marcin1, 3
  • 1 Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland. , (Poland)
  • 2 Institute of Psychiatry and Neurology, 9 Sobieskiego Street, 02-957 Warsaw, Poland. , (Poland)
  • 3 Adamed Pharma S.A., 6A Mariana Adamkiewicza Street, Pienkow, 05-152 Czosnow, Poland. , (Poland)
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Sep 09, 2021
Volume
64
Issue
17
Pages
12603–12629
Identifiers
DOI: 10.1021/acs.jmedchem.1c00497
PMID: 34436892
Source
Medline
Language
English
License
Unknown

Abstract

The current pharmaceutical market lacks therapeutic agents designed to modulate behavioral disturbances associated with dementia. To address this unmet medical need, we designed multifunctional ligands characterized by a nanomolar affinity for clinically relevant targets that are associated with the disease pathology, namely, the 5-HT2A/6/7 and D2 receptors. Compounds that exhibited favorable functional efficacy, water solubility, and metabolic stability were selected for more detailed study. Pharmacological profiling revealed that compound 11 exerted pronounced antidepressant activity (MED 0.1 mg/kg), outperforming commonly available antidepressant drugs, while compound 16 elicited a robust anxiolytic activity (MED 1 mg/kg), exceeding comparator anxiolytics. In contrast to the existing psychotropic agents tested, the novel chemotypes did not negatively impact cognition. At a chronic dose regimen (25 days), 11 did not induce significant metabolic or adverse blood pressure disturbances. These promising therapeutic-like activities and benign safety profiles make the novel chemotypes potential treatment options for dementia patients.

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