Synthesis of Novel Pyrido[1,2- c ]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT 1A Receptor Ligands

• Published in: International journal of molecular sciences Vol. 22; no. 5
• Main Authors: Król, Marek, Ślifirski, Grzegorz, Kleps, Jerzy, Ulenberg, Szymon, Belka, Mariusz, Bączek, Tomasz, Siwek, Agata, Stachowicz, Katarzyna, Szewczyk, Bernadeta, Nowak, Gabriel, Duszyńska, Beata, Herold, Franciszek
• Format: Journal Article
• Language: English
• Published: Switzerland 26.02.2021
• Subjects: Animals; CHO Cells; Cricetulus; Humans; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Receptor, Serotonin, 5-HT1A - chemistry; Receptor, Serotonin, 5-HT1A - metabolism; Serotonin 5-HT1 Receptor Agonists - chemical synthesis; Serotonin 5-HT1 Receptor Agonists - chemistry; Serotonin 5-HT1 Receptor Agonists - pharmacology; drug design; pyrido[1,2-c]pyrimidines; dual 5-HT1A/SERT activity; antidepressants
• ISSN: 1422-0067

Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a-i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine ( ) derivatives were synthesized. The chemical structures of the new compounds were confirmed by H and C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT receptor of all derivatives in the series ( and ) and generally low binding affinities for the SERT protein, with the exception of compounds and . Extended affinity tests for the receptors D , 5-HT , 5-HT and 5-HT were conducted with regard to selected compounds ( , , and ). All four compounds demonstrated very high affinities for the D and 5-HT receptors. Compounds and also had high affinities for 5-HT , while and held moderate affinities for this receptor. Compounds and were also tested in vivo to identify their functional activity profiles with regard to the 5-HT receptor, with demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for and .