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Herold F, Izbicki L, Chodkowski A, Dawidowski M, Krol M, Kleps J, Turlo J, Wolska I, Nowak G, Stachowicz K, Dybala M, Siwek A, Nowak M, Pieniazek E, Jaronczyk M, Sylte I, Mazurek AP: Novel 4-aryl-pyrido [1,2-c] pyrimidines with dual SSRI and 5-HT1A activity: part 2. Eur J Med Chem. 2009 Nov;44(11):4702-15. Epub 2009 Jul 16.
Derivatives of 4-aryl-5,6,7,8-tetrahydro-pyrido [1,2-c] pyrimidine were synthesized. These compounds contain the 3-(4-piperidyl)-1H-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)-1H-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)-1H-indole group resulted in a considerable decrease in binding affinity. |
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