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ADMET parameters ; 3 ; 5-triazine derivatives ; hydantoin derivatives ; 5-HT6 receptor ; 5-HT7 receptor
Abstract:
This doctoral thesis was focused on “druglikeness” screening for ten ligands of the serotonin 5-HT6 receptor (S-HT6R) and seven ones of the 5-HT7 receptor (5- HT7R), which were selected as highly active and/or selective agents in the search for new CNS drugs. The compounds represented two following chemical families: 1,3,5-triazine derivatives (5-HT6R) and 5-arylhydantoin ones (5-HT7R). Initially, the most important parameters of ADMET in silica for the 17 compounds, using three bioinformatics tools, were estimated. Then, the following in vitro ADMET assays were applied: the membrane permeability PAMPA assay, the affinity for Pglycoprotein assay (Pgp) Pgp-Glo™ Assay Systems, the compounds PPB plasma proteins binding test with TRANSILXL, the metabolic stability assay in human microsomes (HLMs), the influence on cytochrome P-450 isoforms, i.e. 3A4 and 2D6, activities assays, the cytotoxicity MTS and EZ4U tests, the hepatotoxicity assay and the mutagenicity Ames test. As results of the studies, compounds with the best ADMET parameters for both the group of hydantoin and the 1,3,5-triazine derivatives with high affinity and selectivity for 5-HT7 and 5-HT6 receptors, respectively, were identified. Among the ligands of the 5-HT6 receptor, the compounds MST-4 and TR-37 turned out the most promising in the light of the in vitro tests results. In the case of 5-H ; T7R antagonists, the best parameters of drug-likeness were achieved by MF-8 and KKB-16.
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Rada Dyscypliny Nauki farmaceutyczne
Promoter:
Handzlik, Jadwiga ; Latacz, Gniewomir