Kondej, MagdaWróbel, Tomasz M.Targowska-Duda, Katarzyna M.Martínez Rodríguez, Antón LeandroKoszła, OliwiaStępnicki, PiotrZięba, AgataPaz, AlbaWronikowska-Denysiuk, OlgaLoza García, María IsabelCastro Pérez, María de los ÁngelesKaczor, Agnieszka A.2025-02-032025-02-032022-06-17Kondej, M., Wróbel, T. M., Targowska-Duda, K. M., Leandro Martínez, A., Koszła, O., Stępnicki, P., Zięba, A., Paz, A., Wronikowska-Denysiuk, O., Loza, M. I., Castro, M., & Kaczor, A. A. (2022). Multitarget Derivatives of D2AAK1 as Potential Antipsychotics: The Effect of Substitution in the Indole Moiety. ChemMedChem, 17(15), e202200238.1860-7179https://hdl.handle.net/10347/39461Schizophrenia is a complex disease which is best treated with multitarget drugs, such as atypical antipsychotics. Previously, using structure-based virtual screening, we found a virtual hit, D2AAK1, with nanomolar affinity for dopamine and serotonin receptors important in schizophrenia pharmacotherapy. As a part of an optimization campaign of D2AAK1, we obtained 17 derivatives that also display a multitarget profile. Selected compounds were tested against off-targets in schizophrenia, i. e., histamine H1 receptor and muscarinic M1 receptor, and these did not display considerable affinity for these receptors. The 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 these compounds was rationalized using molecular modeling.engThis is the peer reviewed version of the following article: Kondej, M., et al. (2022). Multitarget Derivatives of D2AAK1 as Potential Antipsychotics: The Effect of Substitution in the Indole Moiety. ChemMedChem, 17(15), e202200238, which has been published in final form at https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/cmdc.202200238. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.http://creativecommons.org/licenses/by-nc-nd/4.0/AntipsychoticsBehavioral studiesG protein-coupled receptorsMultitarget drugsSchizophrenia3209 Farmacología2390 Química farmacéuticajournal article10.1002/cmdc.202200238open access