New Triazine Derivatives as Serotonin 5-HT6 Receptor Ligands
-
Published:2023-01-22
Issue:3
Volume:28
Page:1108
-
ISSN:1420-3049
-
Container-title:Molecules
-
language:en
-
Short-container-title:Molecules
Author:
Łażewska Dorota1ORCID, Więcek Małgorzata1, Satała Grzegorz2, Chałupnik Paulina1ORCID, Żesławska Ewa3ORCID, Honkisz-Orzechowska Ewelina1ORCID, Tarasek Monika1, Latacz Gniewomir1ORCID, Nitek Wojciech4, Szymańska Ewa1ORCID, Handzlik Jadwiga1ORCID
Affiliation:
1. Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Kraków, Poland 2. Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland 3. Institute of Biology, Pedagogical University of Krakow, Podchorążych 2, 30-084 Kraków, Poland 4. Faculty of Chemistry, Jagiellonian University in Kraków, Gronostajowa 2, 30-387 Kraków, Poland
Abstract
Since the number of people with Alzheimer’s disease (AD) continues to rise, new and effective drugs are urgently needed to not only slow down the progression of the disease, but to stop or even prevent its development. Serotonin 5-HT6 receptor (5-HT6R) ligands are still a promising therapeutic target for the treatment of AD. 1,3,5-Triazine derivatives, as novel structures lacking an indole or a sulfone moiety, have proven to be potent ligands for this receptor. In present work, new derivatives of the compound MST4 (4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine), the potent 5-HT6R antagonist (Ki = 11 nM) with promising ADMET and in vivo properties, were designed. The synthesized compounds were tested for their affinity towards 5-HT6R and other receptor (off)targets (serotonin 5-HT2A, 5-HT7 and dopamine D2). Based on the new results, 4-(2-tert-butylphenoxy)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) was selected for extended in vitro studies as a potent and selective 5-HT6R ligand (Ki = 13 nM). Its ability to permeate the blood–brain barrier (BBB) and its hepatotoxicity were evaluated. In addition, X-ray crystallography and solubility studies were also performed. The results obtained confirm that 6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine derivatives, especially compound 3, are promising structures for further pharmacological studies as 5-HT6R ligands.
Funder
National Science Center
Subject
Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science
Reference32 articles.
1. Alzheimer’s disease;Scheltens;Lancet,2021 2. Pardo-Moreno, T., González-Acedo, A., Rivas-Domínguez, A., García-Morales, V., García-Cozar, F.J., Ramos-Rodríguez, J.J., and Melguizo-Rodríguez, L. (2022). Therapeutic Approach to Alzheimer’s Disease: Current Treatments and New Perspectives. Pharmaceutics, 14. 3. Three FDA advisory panel members resign over approval of Alzheimer’s drug;Mahase;BMJ,2021 4. Aducanumab: Appropriate Use Recommendations;Cummings;J. Prev. Alzheimer’s Dis.,2021 5. U.S. Food & Drug Administration (2022, November 29). Available online: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=212304.
Cited by
3 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|