title: Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT(1A) activity. Part 5.
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.
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Gomółka
authors.affiliation: Pharmaceutical Research Institute, 8, Rydygiera Street, 01-793 Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Ciesielska
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, Poland.
authors.forename: Martyna Z
authors.initials: MZ
authors.lastname: Wróbel
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Chodkowski
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Kleps
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Dawidowski
authors.affiliation: Chair of Pharmacobiology, Jagiellonian University Medical College, 9, Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.affiliation: Chair of Pharmacobiology, Jagiellonian University Medical College, 9, Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Wolak
authors.affiliation: Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, 12, Smętna Street, 31-343 Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Stachowicz
authors.affiliation: Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, 12, Smętna Street, 31-343 Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Sławińska
authors.affiliation: 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.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nowak
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12, Smętna Street, 31-343 Kraków, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Satała
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12, Smętna Street, 31-343 Kraków, Poland.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.affiliation: Department of Pharmaceutical Chemistry, Medical University of Gdańsk, 107, J. Hallera Street, 80-416 Gdańsk, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Belka
authors.affiliation: Department of Pharmaceutical Chemistry, Medical University of Gdańsk, 107, J. Hallera Street, 80-416 Gdańsk, Poland.
authors.forename: Szymon
authors.initials: S
authors.lastname: Ulenberg
authors.affiliation: Department of Pharmaceutical Chemistry, Medical University of Gdańsk, 107, J. Hallera Street, 80-416 Gdańsk, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bączek
authors.affiliation: The Infant Jesus Teaching Hospital, Medical University of Warsaw, 4, Lindleya Street, 02-005 Warsaw, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Skowronek
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, Poland.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Turło
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, Poland. Electronic address: franciszek.herold@wum.edu.pl.
authors.forename: Franciszek
authors.initials: F
authors.lastname: Herold
mesh_terms: D000818:Animals; D008297:Male; D051379:Mice; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011743:Pyrimidines; D044282:Receptor, Serotonin, 5-HT1A; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Antidepressants; Dual SSRI/5-HT(1A) activity; Pyrido[1,2-c]pyrimidines; Quinoline derivatives