Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity, part 1

Franciszek Herold; Andrzej Chodkowski; Łukasz Izbicki; Marek Król; Jerzy Kleps; Jadwiga Turło; Gabriel Nowak; Katarzyna Stachowicz; Małgorzata Dybała; Agata Siwek

doi:10.1016/j.ejmech.2008.09.021

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity, part 1

Eur J Med Chem. 2009 Apr;44(4):1710-7. doi: 10.1016/j.ejmech.2008.09.021. Epub 2008 Sep 30.

Authors

Franciszek Herold¹, Andrzej Chodkowski, Łukasz Izbicki, Marek Król, Jerzy Kleps, Jadwiga Turło, Gabriel Nowak, Katarzyna Stachowicz, Małgorzata Dybała, Agata Siwek

Affiliation

¹ Department of Drug Technology, Faculty of Pharmacy, Medical University of Warsaw, ul. Banacha 1, 02-097 Warszawa, Poland.

PMID: 18995929
DOI: 10.1016/j.ejmech.2008.09.021

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.

Publication types

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

MeSH terms

Animals
Body Temperature / drug effects
Drug Design*
Hypothermia / chemically induced
Hypothermia / drug therapy
Immobilization
Ligands
Male
Mice
Piperazine
Piperazines / chemistry
Piperazines / pharmacology
Piperazines / therapeutic use
Pyridines / pharmacology
Pyridines / therapeutic use
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / metabolism
Pyrimidines / pharmacology*
Receptor, Serotonin, 5-HT1A / metabolism
Selective Serotonin Reuptake Inhibitors / chemical synthesis
Selective Serotonin Reuptake Inhibitors / chemistry*
Selective Serotonin Reuptake Inhibitors / metabolism
Selective Serotonin Reuptake Inhibitors / pharmacology*
Serotonin 5-HT1 Receptor Agonists*
Serotonin Plasma Membrane Transport Proteins / metabolism
Swimming

Substances

Ligands
Piperazines
Pyridines
Pyrimidines
Serotonin 5-HT1 Receptor Agonists
Serotonin Plasma Membrane Transport Proteins
Serotonin Uptake Inhibitors
Receptor, Serotonin, 5-HT1A
Piperazine
N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide