231615-21-7Relevant articles and documents
Novel 4-aryl-pyrido[1,2-c ]pyrimidines with dual SSRI and 5-HT1A activity. Part 4
Chodkowski, Andrzej,Wróbel, Martyna Z.,Turlo, Jadwiga,Kleps, Jerzy,Siwek, Agata,Nowak, Gabriel,Belka, Mariusz,Baczek, Tomasz,Mazurek, Aleksander P.,Herold, Franciszek
, p. 21 - 32 (2015)
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.
Synthesis of novel pyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT1A receptor ligands
?lifirski, Grzegorz,Król, Marek,Kleps, Jerzy,Ulenberg, Szymon,Belka, Mariusz,B?czek, Tomasz,Siwek, Agata,Stachowicz, Katarzyna,Szewczyk, Bernadeta,Nowak, Gabriel,Bojarski, Andrzej,Kozio?, Anna E.,Tur?o, Jadwiga,Herold, Franciszek
, p. 144 - 158 (2019/01/30)
The study enabled obtaining a number of new derivatives of 4-aryl-pyrido[1,2-c]pyrimidine 9.1–9.27 having conformationally restricted tryptamine moiety. In vitro studies (RBA) have shown that derivatives 9.1, 9.2, 9.4, 9.7, 9.9, 9.14 and 9.27 exhibit high affinity to molecular targets 5-HT1A receptor and SERT protein. In general, compounds with an unsubstituted or a para-substituted benzene ring of the pyrido[1,2-c]pyrimidine residue in the terminal part were characterized by higher binding ability, which can be justified by the greater flexibility of the structure. For the selected compounds 9.1, 9.7, 9.9 and 9.27, further in vitro, in vivo and metabolic stability tests were performed. The in vitro studies in the extended receptor profile (D2, 5-HT2A, 5-HT6 and 5-HT7) indicated their selectivity toward the 5-HT1A receptor and SERT protein. The in vivo studies (8-OH-DPAT-induced hypothermia in mice, FST) revealed that the compound 9.1 has the properties of presynaptic agonist of the 5-HT1A receptor, and compound 9.7 demonstrated the properties of a presynaptic antagonist of the 5-HT1A receptor. Metabolic stability studies, in turn, showed that compounds 9.1, 9.7 and 9.9, having an unsubstituted indole residue, were more resistant to biotransformation reactions of the first pass phase than was compound 9.27 containing a 5-methoxy-substituted indole residue. The obtained results allowed further optimization of the structure.
Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity. part 5
Gomolka, Anna,Ciesielska, Agnieszka,Wróbel, Martyna Z.,Chodkowski, Andrzej,Kleps, Jerzy,Dawidowski, MacIej,Siwek, Agata,Wolak, Malgorzata,Stachowicz, Katarzyna,Slawinska, Anna,Nowak, Gabriel,Satala, Grzegorz,Bojarski, Andrzej J.,Belka, Mariusz,Ulenberg, Szymon,Baczek, Tomasz,Skowronek, Pawel,Turlo, Jadwiga,Herold, Franciszek
, p. 221 - 236 (2015/06/08)
A series of novel 4-aryl-pyrido[1,2-c]pyrimidine derivatives containing a 1-(2-quinoline)piperazine moiety was synthesized. The chemical structure of new compounds was confirmed by FT-IR, 1H NMR, 13C NMR and HRMS spectra as well as elemental analysis. Affinity of the novel pyrido[1,2-c]pyrimidine derivatives for 5-HT1A, 5-HT2A receptors and serotonin transporter (SERT) was evaluated in an in vitro radioligand binding assay. Tested compounds showed moderate to high affinity for 5-HT1AR and SERT and low affinity for 5-HT2AR. Selected ligands were subjected to in vivo tests, such as induced hypothermia and the forced swimming test in mice, which determined presynaptic agonistic activity of the ligands 8d, 8e, 9d and 9e and presynaptic antagonistic activity of the ligands 8a, 8b, 9a, 9b. Additionally, metabolic stability evaluation was performed for selected ligands, proving that a para-substitution in the 4-aryl-pyrido[1,2-c]pyrimidine moiety leads to an increase in stability, whereas a substitution in the ortho-position lowers the stability.
