title: Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity. Part 4.
abstract: 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 = 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 = 12.4 nM; Ki SERT = 15.6 nM 8.1; Ki 5-HT1A = 5.6 nM; Ki SERT = 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.
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warszawa, 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 Warszawa, Poland. Electronic address: martynawrobel.wum@gmail.com.
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 Warszawa, 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 Warszawa, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Kleps
authors.affiliation: Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.affiliation: Department of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland; 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 Pharmaceutical Chemistry, Faculty of Pharmacy with Subfaculty of Laboratory Medicine, Medical University of Gdańsk, 107 Al. Gen. J. Hallera Street, 80-416 Gdańsk, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Belka
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy with Subfaculty of Laboratory Medicine, Medical University of Gdańsk, 107 Al. Gen. J. Hallera Street, 80-416 Gdańsk, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bączek
authors.affiliation: Department of Drug Chemistry, Medical University of Warsaw, 1 Banacha Street, 02-097 Warszawa, Poland; National Medicines Institute, 30/34 Chełmska Street, 00-725 Warszawa, Poland.
authors.forename: Aleksander P
authors.initials: AP
authors.lastname: Mazurek
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warszawa, Poland. Electronic address: franciszek.herold@wum.edu.pl.
authors.forename: Franciszek
authors.initials: F
authors.lastname: Herold
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D011743:Pyrimidines; D044282:Receptor, Serotonin, 5-HT1A; D017367:Selective Serotonin Reuptake Inhibitors; C483405:octahydropyrido(1,2-c)pyrimidine
keywords: ADME; Antidepressants; Dual 5-HT(1A)/SERT activity; Pyrido[1,2-c]pyrimidines