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- Title
In the search for a lead structure among series of potent and selective hydantoin 5- HT<sub>7</sub>R agents: The drug-likeness in vitro study.
- Authors
Latacz, Gniewomir; Lubelska, Annamaria; Jastrzębska‐Więsek, Magdalena; Partyka, Anna; Sobiło, Andrzej; Olejarz, Agnieszka; Kucwaj‐Brysz, Katarzyna; Satała, Grzegorz; Bojarski, Andrzej J.; Wesołowska, Anna; Kieć‐Kononowicz, Katarzyna; Handzlik, Jadwiga
- Abstract
Since the year 1993, when 5- HT7 receptor (5- HT7R) was discovered, there is no selective 5- HT7R ligand introduced to the pharmaceutical market. One out of the main reasons disqualifying the 5- HT7R ligands is weak drugability properties, including metabolic instability or low permeability. This study is focused on the search of a lead compound by 'drug-likeness' estimation of the first series of selective and potent 5- HT7R ligands among 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-aryl-piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione derivatives ( 11-16). The most important drugability parameters, i.e., permeability, metabolic stability, and safety, have been evaluated. The main metabolic pathways were determined. The forced swim test ( FST) in mice was performed as a primary in vivo assay for compound 13 and the reference 2. The experiments showed promising drug-like properties for all ligands, with special attention to the benzhydryl (diphenylmethyl) derivative 13. The studies have also indicated in vivo activity of the compound 13 that was observed as a significant and specific antidepressant-like activity in the FST. Taking into account the beneficial properties of 13, i.e., good drug-like parameters, the significant antagonistic action, high selectivity to 5- HT7R, and its in vivo antidepressant-like activity, the compound should be considered as a new lead in the search for drugs acting on CNS via 5- HT7 receptor.
- Subjects
HYDANTOIN; HYDANTOINASE; CANNABINOID receptors; CARBOXAMIDES; PHYSIOLOGICAL effects of antidepressants
- Publication
Chemical Biology & Drug Design, 2017, Vol 90, Issue 6, p1295
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.13106