Chemical puzzles in the search for new, flexible derivatives of lurasidone as antipsychotic drugs
Authors:
- Przemysław Zaręba,
- Anna K. Drabczyk,
- Jolanta Jaśkowska,
- Grzegorz Satała
Abstract
In the pharmacotherapy of schizophrenia, there is a lack of effective drugs, and currently used agents cause a large number of side effects. The D2, 5-HT1A, 5-HT2A receptors are among the most important receptor targets in the treatment of schizophrenia, but antagonism at 5-HT6 and 5-HT7 receptors may bring about additional improvement of cognitive functions. However, doubt exists regarding the importance of 5-HT7R in the pharmacotherapy. In 2010, lurasidone (with high affinity for D2, D3, 5-HT1A, 5-HT2A, 5-HT7 receptors) was approved for the treatment of schizophrenia. Due to the efficacy of the mentioned drug and doubts related to the role of 5-HT7R, we decided to obtain compounds with an activity profile similar to that of lurasidone, but with the reduced affinity for 5-HT7R and increased affinity for 5-HT6R. For this purpose, we chose a flexible hexyl derivative of lurasidone (2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione 1a) as a hit structure. After molecular modeling, we modified it, in the area of the arylpiperazine and imide group, using the moieties found in other known CNS drugs. We received the compounds in accordance with the previously developed method of ecological synthesis in the microwave radiation field. Among the obtained compounds, N-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)naphthalene-sulfonamides 1v and 1w were distinguished as multifunctional ligands showing increased affinity for 5-HT6R, and 2-(6-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one 1i – a multifunctional ligand showing moderate affinity for 5-HT6R and threefold lower for 5-HT7R. In the paper, we discuss some of the observed dependencies regarding 5-HT6/5-HT7R affinity using molecular docking methods.
- Record ID
- CUTec6403bf19c64bd8b37626d932807739
- Publication categories
- ;
- Author
- Journal series
- Bioorganic & Medicinal Chemistry, ISSN 0968-0896, e-ISSN 1464-3391
- Issue year
- 2020
- Vol
- 28
- No
- 10
- Pages
- [1-13]
- Article number
- 115459
- Other elements of collation
- schem.; tab.; Bibliografia (na s.) - 12-13; Bibliografia (liczba pozycji) - 45; Oznaczenie streszczenia - Abstr.; Numeracja w czasopiśmie - Vol. 28, Iss. 10
- Keywords in English
- serotonin receptors, microwave, lurasidone, dopamine, schizophrenia
- DOI
- DOI:10.1016/j.bmc.2020.115459 Opening in a new tab
- URL
- https://www.sciencedirect.com/science/article/pii/S096808962030273X?via%3Dihub 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)
- 70
- Additional fields
- Indeksowana w: Web of Science, Scopus
- Uniform Resource Identifier
- https://cris.pk.edu.pl/info/article/CUTec6403bf19c64bd8b37626d932807739/
- URN
urn:pkr-prod:CUTec6403bf19c64bd8b37626d932807739
* presented citation count is obtained through Internet information analysis, and it is close to the number calculated by the Publish or PerishOpening in a new tab system.