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N-Skatyltryptamines—Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential

N-Skatyltryptamines—Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential

Authors :
Agata Hogendorf
Adam S. Hogendorf
Rafał Kurczab
Grzegorz Satała
Bernadeta Szewczyk
Paulina Cieślik
Gniewomir Latacz
Jadwiga Handzlik
Tomasz Lenda
Katarzyna Kaczorowska
Jakub Staroń
Ryszard Bugno
Beata Duszyńska
Andrzej J. Bojarski
Source :
Molecules, Vol 26, Iss 15, p 4605 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous—in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.

Details

Language :
English
ISSN :
14203049
Volume :
26
Issue :
15
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.161dfe1128284230be1a6f666c15721d
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules26154605