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

Abstract

Derivatives of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2- c]pyrimidine were synthesized. These compounds contain the 3-(4-piperidyl)-1 H-indole residue or its 5-methoxy or 2-methyl derivative. In vitro binding tests were performed to determine the affinity of the compounds for the 5-HT 1A receptor and serotonin transporter (SERT) proteins in the rat brain cortex. In vivo studies, particularly the inducible hypothermia test and forced swimming test, were conducted to determine agonistic/antagonistic activity with pre- and postsynaptic 5-HT 1A receptors. Molecular modeling techniques were used to determine the binding modes of the selected compounds at the 5-HT 1A receptor and SERT. The SAR analysis showed that the presence of the 3-(4-piperidyl)-1 H-indole group or its 5-methoxy derivative, as well as a para substitution with –OCH 3 or –F in the aryl ring of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2- c]pyrimidine, results in an increased affinity for both the 5-HT 1A receptors and SERT. In contrast, the presence of the 2-methyl-3-(4-piperidyl)-1 H-indole group resulted in a considerable decrease in binding affinity.