title: Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity, part 1.
abstract: A series of new derivatives of 4-aryl-pyrido[1,2-c]pyrimidine containing the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy derivative were synthesized. They were characterized (i) in vitro by binding to 5-HT(1A) receptors and 5-HT transporter proteins in rat brain cortex membranes and (ii) in vivo in the mouse by induced hypothermia and forced swimming models for antagonist/agonist activity against the 5-HT(1A) autoreceptors and postsynaptic 5-HT(1A) receptors, respectively. Structure activity relationship evaluation indicated that the presence of the 3-(4-piperidyl)-1H-indole residue and ortho- or para-substituents with -F or -CH(3) groups in the aryl ring as well as an unsubstituted aryl in the 4-aryl-pyrido[1,2-c]pyrimidine moiety promoted low K(i) values for both receptors. In contrast, the presence of a 5-methoxy-3-(4-piperidyl)-1H-indole residue as well as -Cl or -OCH(3) substituents at the para position markedly reduced the receptor affinity.
authors.affiliation: Department of Drug Technology, Faculty of Pharmacy, Medical University of Warsaw, ul. Banacha 1, 02-097 Warszawa, Poland.
authors.forename: Franciszek
authors.initials: F
authors.lastname: Herold
authors.forename: Andrzej
authors.initials: A
authors.lastname: Chodkowski
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Izbicki
authors.forename: Marek
authors.initials: M
authors.lastname: Król
authors.forename: Jerzy
authors.initials: J
authors.lastname: Kleps
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Turło
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nowak
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Stachowicz
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Dybała
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D015195:Drug Design; D007035:Hypothermia / Q000139:chemically induced / Q000188:drug therapy; D007103:Immobilization; D008024:Ligands; D008297:Male; D051379:Mice; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013550:Swimming
chemical_list: D008024:Ligands; D000077489:Piperazine; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D044282:Receptor, Serotonin, 5-HT1A; D058825:Serotonin 5-HT1 Receptor Agonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide