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Open AccessArticle

Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro

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Department of Technology and Biotechnology of Drugs, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland
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Department of Clinical Pharmacy, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland
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Department of Pharmacodynamics, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland
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Department of Medicinal Chemistry Maj Institute of Pharmacology, Polish Academy of Science, Smętna 12, PL 31-343 Cracow, Poland
*
Author to whom correspondence should be addressed.
Academic Editors: Pedro A. Sánchez-Murcia, Alba Gigante and Víctor Sebastián Pérez
Molecules 2019, 24(24), 4472; https://doi.org/10.3390/molecules24244472
Received: 21 October 2019 / Revised: 21 November 2019 / Accepted: 3 December 2019 / Published: 6 December 2019
Though the 5-HT6 serotonin receptor is an important target giving both agonists and antagonists similar therapeutic potency in the treatment of topic CNS-diseases, no 5-HT6R ligand has reached the pharmaceutical market yet due to the too narrow chemical space of the known 5-HT6R agents and insufficient “drugability.” Recently, a new group of non-indole and non-sulfone hydantoin-triazine 5-HT6R ligands was found, where 3-((4-amino-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-yl)methyl)-5-methyl-5-(naphthalen-2-yl)imidazolidine-2,4-dione (KMP-10) was the most active member. This study is focused on wider pharmacological and “druglikeness” characteristics for KMP-10. A computer-aided insight into molecular interactions with 5-HT6R has been performed. “Druglikeness” was examined using an eight-test panel in vitro, i.e., a parallel artificial membrane permeability assay (PAMPA), and Caco-2 permeability-, P-glycoprotein (Pgp) affinity-, plasma protein binding-, metabolic stability- and drug–drug interaction-assays, as well as mutagenicity- and HepG2-hepatotoxicity risk tests. Behavioral studies in vivo, i.e., elevated plus-maze (EPM) and novel object recognition (NOR) tests, were performed. Extended studies on the influence of KMP-10 on rats’ metabolism, including biochemical tests, were conducted in vivo. Results indicated significant anxiolytic and precognitive properties, as well as some anti-obesity properties in vivo, and it was found to satisfy the “druglikeness” profile in vitro for KMP-10. The compound seems to be a good lead-structure and candidate for wider pharmacological studies in search for new CNS-drugs acting via 5-HT6R. View Full-Text
Keywords: 5-HT6R antagonist; 1,3,5-triazine; hydantoin; ADME-Tox parameters; procognitive effect; obesity 5-HT6R antagonist; 1,3,5-triazine; hydantoin; ADME-Tox parameters; procognitive effect; obesity
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Lubelska, A.; Latacz, G.; Jastrzębska-Więsek, M.; Kotańska, M.; Kurczab, R.; Partyka, A.; Marć, M.A.; Wilczyńska, D.; Doroz-Płonka, A.; Łażewska, D.; Wesołowska, A.; Kieć-Kononowicz, K.; Handzlik, J. Are the Hydantoin-1,3,5-triazine 5-HT6R Ligands a Hope to a Find New Procognitive and Anti-Obesity Drug? Considerations Based on Primary In Vivo Assays and ADME-Tox Profile In Vitro. Molecules 2019, 24, 4472.

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