Synthesis of new 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT 1A receptor ligands

Extended studies in the 4-aryl-pyrido[1,2-c]pyrimidine group resulted in 27 new compounds (10.1-10.27), 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives. In vitro tests (RBA) were carried out for 10.1-10.27 compounds in order to determine their affinity to 5-HT receptor and SERT protein. 10.1-1...

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Veröffentlicht in:European journal of medicinal chemistry 2019-10, Vol.180, p.383
Hauptverfasser: Ślifirski, Grzegorz, Król, Marek, Kleps, Jerzy, Podsadni, Piotr, Belka, Mariusz, Bączek, Tomasz, Siwek, Agata, Stachowicz, Katarzyna, Szewczyk, Bernadeta, Nowak, Gabriel, Bojarski, Andrzej, Kozioł, Anna E, Turło, Jadwiga, Herold, Franciszek
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Sprache:eng
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Zusammenfassung:Extended studies in the 4-aryl-pyrido[1,2-c]pyrimidine group resulted in 27 new compounds (10.1-10.27), 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives. In vitro tests (RBA) were carried out for 10.1-10.27 compounds in order to determine their affinity to 5-HT receptor and SERT protein. 10.1-10.3, 10.6, 10.7, 10.16 and 10.27 compounds had high binding ability to both molecular targets (5-HT K  = 8-87 nM; SERT K  = 8-52 nM). For these compounds (10.1-10.3, 10.6, 10.7, 10.16, 10.27) further in vitro, in vivo and metabolic stability tests were performed. In vitro studies in the extended receptor profile (D , 5-HT , 5-HT and 5-HT ) showed their selectivity towards 5-HT receptor and SERT protein. In vivo tests revealed that compounds 10.7 and 10.16 had the properties of presynaptic antagonists of the 5-HT receptor. The redesign of the 2H-pyrido[1,2-c]pyrimidine residue present in the terminal part towards 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine resulted in the improved metabolic stability and enhanced affinity to both molecular targets (5-HT -R and SERT) compared to the precursors.
ISSN:1768-3254