New N-aryl-N′-aryl-/(thio)ureido-/sulfamoylamino-derivatives of alkyl/alkylcarbamoyl piperazines: Effect of structural modifications on selectivity over 5-HT1A receptor
Authors:
- Przemysław Zaręba,
- Paweł Śliwa,
- Grzegorz Satała,
- Paweł Zajdel,
- Gniewomir Latacz,
- Jolanta Jaśkowska
Abstract
The 5-HT1A receptors are an important biological target in the treatment of CNS diseases. Recently, their importance in the context of non-CNS disease entities has also been postulated. In the light of these reports, we designed a new group of urea derivatives of N-aryl-N′-aryl-/(thio)ureido-/sulfamoylamino-derivatives of alkyl/alkylcarbamoyl piperazines as 5-HT1AR ligands, focusing on increasing receptor selectivity. We made structural modifications in three areas of the molecule. In the course of our research, we obtained a ligand with reduced basicity (6f), which, despite the loss of the protonable nitrogen atom, did not lose its affinity for the 5-HT1AR (Ki = 35 nM) with a simultaneous increase in selectivity. In particular, a decrease in affinity for D2R (Ki = 1940 nM) was observed, which was analyzed using molecular modeling methods, including FMO and molecular dynamics. Basic ADME-Tox parameters were characterized for 6f, confirming its potential applicability in pharmacotherapy.
- Record ID
- CUTa061b645887a45999a100ce048278581
- Publication categories
- ;
- Author
- Journal series
- European Journal of Medicinal Chemistry, ISSN 0223-5234, e-ISSN 1768-3254
- Issue year
- 2022
- Vol
- 235
- Pages
- [1-17]
- Article number
- 114319
- Other elements of collation
- rys.; tab.; wykr.; Bibliografia (na s.) - 16-17; Bibliografia (liczba pozycji) - 76; Oznaczenie streszczenia - Abstr.; Numeracja w czasopiśmie - Vol. 235
- Keywords in English
- serotonin, dopamine, non-basic, microwave, synthesis, FMO, molecular dynamics, 5-HT1A, ADME, selectivity, urea
- ASJC Classification
- ; ; ;
- DOI
- DOI:10.1016/j.ejmech.2022.114319 Opening in a new tab
- URL
- https://www.sciencedirect.com/science/article/pii/S0223523422002215 Opening in a new tab
- Related project
- Synteza i ocena aktywności nowych ligandów działających na receptory ośrodkowego układu nerwowego (oun). . Project leader at PK: , ,
Projects financed by NCRD [Projekty finansowane przez NCBiR (NCBR (] - Language
- eng (en) English
- License
- Score (nominal)
- 140
- Score source
- journalList
- Score
- Publication indicators
- Additional fields
- Indeksowana w: Web of Science, Scopus
- Uniform Resource Identifier
- https://cris.pk.edu.pl/info/article/CUTa061b645887a45999a100ce048278581/
- URN
urn:pkr-prod:CUTa061b645887a45999a100ce048278581
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