The Phenoxyalkyltriazine Antagonists for 5-HT6 Receptor with Promising Procognitive and Pharmacokinetic Properties In Vivo in Search for a Novel Therapeutic Approach to Dementia Diseases

Autor:	Sylwia Sudoł, Jadwiga Handzlik, Natalia Wilczyńska-Zawal, Gniewomir Latacz, Magdalena Jastrzębska-Więsek, Barbara Mordyl, Agnieszka Cios, Ewelina Honkisz-Orzechowska, Agnieszka Olejarz-Maciej, Grzegorz Satała, Katarzyna Kucwaj-Brysz, Anna Wesołowska, Anna Partyka
Jazyk:	angličtina
Rok vydání:	2021
Předmět:	Drug QH301-705.5 media_common.quotation_subject Pharmacology Catalysis Inorganic Chemistry Pharmacokinetics In vivo 1 3 5-triazine Biology (General) Physical and Theoretical Chemistry Receptor QD1-999 Molecular Biology Spectroscopy 5-HT receptor media_common Chemistry Organic Chemistry General Medicine In vitro Computer Science Applications ADME-Tox parameters procognitive effects Pharmacodynamics 5-HT6 receptor 5-HT6 ligands Alzheimer’s disease
Zdroj:	International Journal of Molecular Sciences Volume 22 Issue 19 International Journal of Molecular Sciences, Vol 22, Iss 10773, p 10773 (2021)
ISSN:	1422-0067
DOI:	10.3390/ijms221910773
Popis:	Among the serotonin receptors, one of the most recently discovered 5-HT6 subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT6 receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT6 receptor. Thus, a broader pharmacological profile for 1–3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, (RS)-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (2) and (RS)-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (3), but insensibly predominant for compound 2. Nevertheless, both compounds (2 and 3) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT6 receptor target.
Databáze:	OpenAIRE
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