Multi-target derivatives of D2AAK1 as potential antipsychotics - the effect of the substitution in the indole moiety

• Published in: ChemMedChem
• Main Authors: Kondej, Magda, Wróbel, Tomasz M, Targowska-Duda, Katarzyna M, Martínez, Antón Leandro, Koszła, Oliwia, Stępnicki, Piotr, Zięba, Agata, Paz, Alba, Wronikowska-Denysiuk, Olga, Loza, Maria I, Castro, Marián, Kaczor, Agnieszka Anna
• Format: Journal Article
• Language: English
• Published: Germany 24-05-2022
• Subjects: G protein-coupled receptors; behavioral studies; antipsychotics; schizophrenia; multi-target drugs
• ISSN: 1860-7187

Schizophrenia is a complex disease which is best treated with multi-target drugs, such as atypical antipsychotics. Previously, using structure-based virtual screening we found a virtual hit D2AAK1 with nanomolar affinity to dopamine and serotonin receptors important in schizophrenia pharmacotherapy. As a part of optimization campaign of D2AAK1 we obtained its 17 derivatives also displaying a multi-target profile. Selected compounds were tested against off-targets in schizophrenia, i.e. histamine H 1 receptor and muscarinic M 1 receptor and did not display considerable affinity to these receptors. Two most promising compounds were subjected to behavioral studies. These compounds decreased amphetamine-induced hyperactivity in mice which indicates their antipsychotic potential. The compounds did not interfere with the memory consolidation in mice as determined in the passive avoidance test. The favorable pharmacological profile of the compounds was rationalized using molecular modeling.