European Journal of Medicinal Chemistry p. 21 - 32 (2015)
Update date:2022-08-15
Topics:
Chodkowski, Andrzej
Wróbel, Martyna Z.
Turlo, Jadwiga
Kleps, Jerzy
Siwek, Agata
Nowak, Gabriel
Belka, Mariusz
Baczek, Tomasz
Mazurek, Aleksander P.
Herold, Franciszek
This project describes the synthesis, pharmacological and pharmacodynamic tests on two series of novel derivatives of 2H-pyrido[1,2-c]pyrimidine with potential binary binding to 5-HT1A receptors and SSRI + serotonin transporters. The influence of piperidinyl-indole (8.1-8.7) and tetrahydropyridinyl-indole (8.8-8.32) residues and indole 5-position substituents (R3 Combining double low line Br, Cl, F) present in the pharmacophore element of ligands on their binding to both molecular targets was tested.A considerable impact of piperidinyl-indole residue on binding to both targets was confirmed and compounds with a high binding affinity were identified: Ki 5-HT1A Combining double low line 12.4 nM; Ki SERT Combining double low line 15.6 nM 8.1; Ki 5-HT1A Combining double low line 5.6 nM; Ki SERT Combining double low line 20.7 nM 8.7, while the presence of a tetrahydropyridinyl-indole residue was found to reduce the affinity of ligands to 5-HT1AR. The presence of chlorine (R3) in this series resulted in a notable reduction in binding to both targets (5-HT1A and SERT). Selected compounds had their metabolic stability in a first-pass test (human liver microsomes, NADPH) determined in vitro, and R1 and R2 substituents present on the terminal residue of pyrido[1,2-c]pyrimidine were recognized as having an impact on stability.
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