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

Anna Gomółka; Agnieszka Ciesielska; Martyna Z Wróbel; Andrzej Chodkowski; Jerzy Kleps; Maciej Dawidowski; Agata Siwek; Małgorzata Wolak; Katarzyna Stachowicz; Anna Sławińska; Gabriel Nowak; Grzegorz Satała; Andrzej J Bojarski; Mariusz Belka; Szymon Ulenberg; Tomasz Bączek; Paweł Skowronek; Jadwiga Turło; Franciszek Herold

doi:10.1016/j.ejmech.2015.05.003

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

Eur J Med Chem. 2015 Jun 15:98:221-36. doi: 10.1016/j.ejmech.2015.05.003. Epub 2015 May 9.

Authors

Anna Gomółka¹, Agnieszka Ciesielska², Martyna Z Wróbel¹, Andrzej Chodkowski¹, Jerzy Kleps¹, Maciej Dawidowski¹, Agata Siwek³, Małgorzata Wolak³, Katarzyna Stachowicz⁴, Anna Sławińska⁴, Gabriel Nowak⁵, Grzegorz Satała⁶, Andrzej J Bojarski⁶, Mariusz Belka⁷, Szymon Ulenberg⁷, Tomasz Bączek⁷, Paweł Skowronek⁸, Jadwiga Turło¹, Franciszek Herold⁹

Affiliations

¹ Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, Poland.
² Pharmaceutical Research Institute, 8, Rydygiera Street, 01-793 Warsaw, Poland.
³ Chair of Pharmacobiology, Jagiellonian University Medical College, 9, Medyczna Street, 30-688 Kraków, Poland.
⁴ Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, 12, Smętna Street, 31-343 Kraków, Poland.
⁵ Chair of Pharmacobiology, Jagiellonian University Medical College, 9, Medyczna Street, 30-688 Kraków, Poland; Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, 12, Smętna Street, 31-343 Kraków, Poland.
⁶ Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12, Smętna Street, 31-343 Kraków, Poland.
⁷ Department of Pharmaceutical Chemistry, Medical University of Gdańsk, 107, J. Hallera Street, 80-416 Gdańsk, Poland.
⁸ The Infant Jesus Teaching Hospital, Medical University of Warsaw, 4, Lindleya Street, 02-005 Warsaw, Poland.
⁹ Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, Poland. Electronic address: [email protected].

PMID: 26043160
DOI: 10.1016/j.ejmech.2015.05.003

Abstract

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, (1)H NMR, (13)C 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.

Keywords: Antidepressants; Dual SSRI/5-HT(1A) activity; Pyrido[1,2-c]pyrimidines; Quinoline derivatives.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Male
Mice
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Radioligand Assay
Receptor, Serotonin, 5-HT1A / drug effects*
Selective Serotonin Reuptake Inhibitors / chemistry
Selective Serotonin Reuptake Inhibitors / pharmacology*

Substances

Pyrimidines
Serotonin Uptake Inhibitors
Receptor, Serotonin, 5-HT1A