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Eur J Med Chem. 2019 Jul 12;180:383-397. doi: 10.1016/j.ejmech.2019.07.027. [Epub ahead of print]

Synthesis of new 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT1A receptor ligands.

Author information

1
Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097, Warszawa, Poland.
2
Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097, Warszawa, Poland. Electronic address: marek.krol@wum.edu.pl.
3
Department of Pharmaceutical Chemistry, Medical University of Gdańsk, 107, J. Hallera Street, 80-416, Gdańsk, Poland.
4
Institute of Pharmacology, Polish Academy of Sciences, 12, Smętna Street, 31-343, Kraków, Poland.
5
Institute of Pharmacology, Polish Academy of Sciences, 12, Smętna Street, 31-343, Kraków, Poland; Chair of Pharmacobiology, Jagiellonian University Medical College, 9, Medyczna Street, 30-688, Kraków, Poland.
6
Faculty of Chemistry, Maria Curie-Skłodowska University, 3, M. Curie-Skłodowskiej Sq., 20-031, Lublin, Poland.

Abstract

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-HT1A 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-HT1A Ki = 8-87 nM; SERT Ki = 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 (D2, 5-HT2A, 5-HT6 and 5-HT7) showed their selectivity towards 5-HT1A receptor and SERT protein. In vivo tests revealed that compounds 10.7 and 10.16 had the properties of presynaptic antagonists of the 5-HT1A 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-HT1A-R and SERT) compared to the precursors.

KEYWORDS:

Antidepressants; Dual 5-HT(1A)/SERT activity; Pyrido[1,2-c]pyrimidines

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