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

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-HT1A 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-HT1A autoreceptors and postsynaptic 5-HT1A 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 -CH3 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 methoxy-3-(4-piperidyl)-1H-indole residue as well as -CI or -OCH3 substituents at the para position markedly reduced the receptor affinity. (c) 2008 Elsevier Masson SAS. All rights reserved.