Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity. Part 5

作者：Gomolka Anna; Ciesielska Agnieszka; Wrobel 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^*

来源：European Journal of Medicinal Chemistry, 2015, 98: 221-236.

DOI：10.1016/j.ejmech.2015.05.003

• Pyrido[1,2-c]pyrimidines
• Antidepressants
• Dual SSRI/5-HT1A activity
• Quinoline derivatives

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, H-1 NMR,C-13 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.

• 出版日期2015-6-15