Simple view

Full metadata view

Authors

Statistics

Synthesis and biological evaluation of novel 3-(5-substituted-1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with a dual affinity for serotonin 5-HT1A receptor and SERT

2023
journal article
article
10.1016/j.bioorg.2023.106903
Journal
Bioorganic Chemistry
140
Author
Wróbel Martyna Z.

Chodkowski Andrzej

Dawidowski Maciej

Siwek Agata

Stachowicz Katarzyna
Show more
Volume
141
Article ID
106903
ISSN
0045-2068
eISSN
1090-2120
Keywords in English

5-HT1A/SERT dual activity

multitarget directed ligand

5-HT1A agonists

serotonin reuptake inhibitors

D2 receptor ligands

antidepressants

URL
https://www.sciencedirect.com/science/article/pii/S0045206823005643?via%3Dihub
Access date
2023-11-14
Language
English
Journal language
English
Abstract in English

The serotonin 1A (5-HT) receptors and serotonin transporter (SERT) are important biological targets in the treatment of diseases of the central nervous system, especially for depression. In this study, new 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives linked with the 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole moiety were synthesised and evaluated for their affinity for 5-HT receptor and serotonin reuptake inhibition. Selected compounds were then tested for their affinity for D, 5-HT, 5-HT and 5-HT receptors, and also in in vitro metabolic stability assays in human microsomes. Finally, in vivo assays allowed us to evaluate the agonist–antagonist properties of pre- and postsynaptic 5-HT receptors. 3-(1-(4-(3-(5-methoxy-1H-indol-3-yl)-2,5-dioxopyrrolidin-1-yl)butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile (4f) emerged as the most promising compound from the series, due to its favourable receptor binding profile (K = 10.0 nM; K = 2.8 nM), good microsomal stability and 5-HT receptor agonistic activity.

Affiliation
Wydział Farmaceutyczny : Zakład RadioligandówWydział Farmaceutyczny : Zakład Cytobiologii
Scopus© citations
3
dc.abstract.enThe serotonin 1A (5-HT$_{1a}$) receptors and serotonin transporter (SERT) are important biological targets in the treatment of diseases of the central nervous system, especially for depression. In this study, new 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives linked with the 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole moiety were synthesised and evaluated for their affinity for 5-HT$_{1a}$ receptor and serotonin reuptake inhibition. Selected compounds were then tested for their affinity for D$_{2}$, 5-HT$_{2a}$, 5-HT$_{6}$ and 5-HT$_{7}$ receptors, and also in in vitro metabolic stability assays in human microsomes. Finally, in vivo assays allowed us to evaluate the agonist–antagonist properties of pre- and postsynaptic 5-HT$_{1a}$ receptors. 3-(1-(4-(3-(5-methoxy-1H-indol-3-yl)-2,5-dioxopyrrolidin-1-yl)butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile (4f) emerged as the most promising compound from the series, due to its favourable receptor binding profile (K$_{i(5-HT1A)}$ = 10.0 nM; K$_{i(SERT)}$ = 2.8 nM), good microsomal stability and 5-HT$_{1a}$ receptor agonistic activity.
dc.affiliationWydział Farmaceutyczny : Zakład Radioligandówpl
dc.affiliationWydział Farmaceutyczny : Zakład Cytobiologiipl
dc.cm.date2023-11-15T07:00:54Z
dc.cm.id113699pl
dc.cm.idOmegaUJCM3d4819f39648469886e9d05dc71b6bbepl
dc.contributor.authorWróbel, Martyna Z.pl
dc.contributor.authorChodkowski, Andrzejpl
dc.contributor.authorDawidowski, Maciejpl
dc.contributor.authorSiwek, Agata - 133399 pl
dc.contributor.authorStachowicz, Katarzynapl
dc.contributor.authorSzewczyk, Bernadetapl
dc.contributor.authorNowak, Gabriel - 132996 pl
dc.contributor.authorSatała, Grzegorzpl
dc.contributor.authorBojarski, Andrzej J.pl
dc.contributor.authorTurło, Jadwigapl
dc.date.accession2023-11-14pl
dc.date.accessioned2023-11-15T07:00:54Z
dc.date.available2023-11-15T07:00:54Z
dc.date.issued2023pl
dc.date.openaccess0
dc.description.accesstimew momencie opublikowania
dc.description.versionostateczna wersja wydawcy
dc.description.volume141pl
dc.identifier.articleid106903pl
dc.identifier.doi10.1016/j.bioorg.2023.106903pl
dc.identifier.eissn1090-2120pl
dc.identifier.issn0045-2068pl
dc.identifier.urihttps://ruj.uj.edu.pl/xmlui/handle/item/323195
dc.identifier.weblinkhttps://www.sciencedirect.com/science/article/pii/S0045206823005643?via%3Dihubpl
dc.languageengpl
dc.language.containerengpl
dc.pbn.affiliationDziedzina nauk medycznych i nauk o zdrowiu : nauki farmaceutyczne
dc.rightsUdzielam licencji. Uznanie autorstwa - Użycie niekomercyjne - Bez utworów zależnych 4.0 Międzynarodowa
dc.rights.licenceCC-BY-NC-ND
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/legalcode.pl
dc.share.typeOtwarte czasopismo
dc.subject.en5-HT1A/SERT dual activity
dc.subject.enmultitarget directed ligand
dc.subject.en5-HT1A agonists
dc.subject.enserotonin reuptake inhibitors
dc.subject.enD2 receptor ligands
dc.subject.enantidepressants
dc.subtypeArticlepl
dc.titleSynthesis and biological evaluation of novel 3-(5-substituted-1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with a dual affinity for serotonin 5-HT1A receptor and SERTpl
dc.title.journalBioorganic Chemistrypl
dc.typeJournalArticlepl
dspace.entity.typePublication
dc.abstract.en
The serotonin 1A (5-HT$_{1a}$) receptors and serotonin transporter (SERT) are important biological targets in the treatment of diseases of the central nervous system, especially for depression. In this study, new 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives linked with the 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole moiety were synthesised and evaluated for their affinity for 5-HT$_{1a}$ receptor and serotonin reuptake inhibition. Selected compounds were then tested for their affinity for D$_{2}$, 5-HT$_{2a}$, 5-HT$_{6}$ and 5-HT$_{7}$ receptors, and also in in vitro metabolic stability assays in human microsomes. Finally, in vivo assays allowed us to evaluate the agonist–antagonist properties of pre- and postsynaptic 5-HT$_{1a}$ receptors. 3-(1-(4-(3-(5-methoxy-1H-indol-3-yl)-2,5-dioxopyrrolidin-1-yl)butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile (4f) emerged as the most promising compound from the series, due to its favourable receptor binding profile (K$_{i(5-HT1A)}$ = 10.0 nM; K$_{i(SERT)}$ = 2.8 nM), good microsomal stability and 5-HT$_{1a}$ receptor agonistic activity.
dc.affiliationpl
Wydział Farmaceutyczny : Zakład Radioligandów
dc.affiliationpl
Wydział Farmaceutyczny : Zakład Cytobiologii
dc.cm.date
2023-11-15T07:00:54Z
dc.cm.idpl
113699
dc.cm.idOmegapl
UJCM3d4819f39648469886e9d05dc71b6bbe
dc.contributor.authorpl
Wróbel, Martyna Z.
dc.contributor.authorpl
Chodkowski, Andrzej
dc.contributor.authorpl
Dawidowski, Maciej
dc.contributor.authorpl
Siwek, Agata - 133399
dc.contributor.authorpl
Stachowicz, Katarzyna
dc.contributor.authorpl
Szewczyk, Bernadeta
dc.contributor.authorpl
Nowak, Gabriel - 132996
dc.contributor.authorpl
Satała, Grzegorz
dc.contributor.authorpl
Bojarski, Andrzej J.
dc.contributor.authorpl
Turło, Jadwiga
dc.date.accessionpl
2023-11-14
dc.date.accessioned
2023-11-15T07:00:54Z
dc.date.available
2023-11-15T07:00:54Z
dc.date.issuedpl
2023
dc.date.openaccess
0
dc.description.accesstime
w momencie opublikowania
dc.description.version
ostateczna wersja wydawcy
dc.description.volumepl
141
dc.identifier.articleidpl
106903
dc.identifier.doipl
10.1016/j.bioorg.2023.106903
dc.identifier.eissnpl
1090-2120
dc.identifier.issnpl
0045-2068
dc.identifier.uri
https://ruj.uj.edu.pl/xmlui/handle/item/323195
dc.identifier.weblinkpl
https://www.sciencedirect.com/science/article/pii/S0045206823005643?via%3Dihub
dc.languagepl
eng
dc.language.containerpl
eng
dc.pbn.affiliation
Dziedzina nauk medycznych i nauk o zdrowiu : nauki farmaceutyczne
dc.rights
Udzielam licencji. Uznanie autorstwa - Użycie niekomercyjne - Bez utworów zależnych 4.0 Międzynarodowa
dc.rights.licence
CC-BY-NC-ND
dc.rights.uri
http://creativecommons.org/licenses/by-nc-nd/4.0/legalcode.pl
dc.share.type
Otwarte czasopismo
dc.subject.en
5-HT1A/SERT dual activity
dc.subject.en
multitarget directed ligand
dc.subject.en
5-HT1A agonists
dc.subject.en
serotonin reuptake inhibitors
dc.subject.en
D2 receptor ligands
dc.subject.en
antidepressants
dc.subtypepl
Article
dc.titlepl
Synthesis and biological evaluation of novel 3-(5-substituted-1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with a dual affinity for serotonin 5-HT1A receptor and SERT
dc.title.journalpl
Bioorganic Chemistry
dc.typepl
JournalArticle
dspace.entity.type
Publication
Affiliations
Wydział Farmaceutyczny
Siwek, Agata
Nowak, Gabriel
No affiliation
Wróbel, Martyna Z.
Chodkowski, Andrzej
Dawidowski, Maciej
Stachowicz, Katarzyna
Szewczyk, Bernadeta
Satała, Grzegorz
Bojarski, Andrzej J.
Turło, Jadwiga

* The migration of download and view statistics prior to the date of April 8, 2024 is in progress.

Views
18
Views per month
Views per city
Krakow
6
Downloads
siwek_et-al_synthesis_and_biological_evaluation_of_novel_2023.pdf
222

Open Access

No Thumbnail Available
License
CC-BY-NC-ND

Except as otherwise noted, this item is licensed under : Udzielam licencji. Uznanie autorstwa - Użycie niekomercyjne - Bez utworów zależnych 4.0 Międzynarodowa

Collections
Publications of the Medical College
Medical sciences
Research publications