Synthesis and In Vitro Evaluation of Novel Dopamine Receptor D2 3,4-dihydroquinolin-2(1H)-one Derivatives Related to Aripiprazole

Biomolecules

Marko Mecava¹  Lenka Pulkrabkova¹  Lukas Prchal¹  Lubica Muckova¹  Tereza Kobrlova¹  Ondrej Soukup¹  Wim Dehaen²  Kamil Musilek³  Alena Randakova⁴  Tomas Petrasek⁵  Iveta Vojtechova⁵  Eva Mezeiova⁵  Kristyna Stefkova⁵  Jan Korabecny⁵  Radomir Juza⁵ 

[1] Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic;CZ-OPENSCREEN: National Infrastructure for Chemical Biology, Department of Informatics and Chemistry, Faculty of Chemical Technology, University of Chemistry and Technology Prague, Technicka 5, 166 28 Prague, Czech Republic;Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic;Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic;National Institute of Mental Health, Topolova 748, 250 67 Klecany, Czech Republic;

关键词: aripiprazole;    dopamine receptor;    blood–brain barrier;    molecular modeling studies;    schizophrenia;   

DOI  :  10.3390/biom11091262

来源: DOAJ

【 摘 要 】

In this pilot study, a series of new 3,4-dihydroquinolin-2(1H)-one derivatives as potential dopamine receptor D₂ (D₂R) modulators were synthesized and evaluated in vitro. The preliminary structure–activity relationship disclosed that compound 5e exhibited the highest D₂R affinity among the newly synthesized compounds. In addition, 5e showed a very low cytotoxic profile and a high probability to cross the blood–brain barrier, which is important considering the observed affinity. However, molecular modelling simulation revealed completely different binding mode of 5e compared to USC-D301, which might be the culprit of the reduced affinity of 5e toward D₂R in comparison with USC-D301.

【 授权许可】

Unknown