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

Abstract This project describes the synthesis, pharmacological and pharmacodynamic tests on two series of novel derivatives of 2H-pyrido[ 1 , 2 - c ]pyrimidine with potential binary binding to 5-HT 1A receptors and SSRI + serotonin transporters. The influence of piperidinyl-indole ( 8.1 – 8.7 ) and tetrahydropyridinyl-indole ( 8.8 – 8.32 ) residues and indole 5-position substituents ( R 3  = Br, Cl, F) present in the pharmacophore element of ligands on their binding to both molecular targets was tested. A considerable impact of piperidinyl-indole residue on binding to both targets was confirmed and compounds with a high binding affinity were identified: K i 5-HT 1A  = 12.4 nM; K i SERT = 15.6 nM 8.1 ; K i 5-HT 1A  = 5.6 nM; K i SERT = 20.7 nM 8.7 , while the presence of a tetrahydropyridinyl-indole residue was found to reduce the affinity of ligands to 5-HT 1A R. The presence of chlorine (R 3 ) in this series resulted in a notable reduction in binding to both targets (5-HT 1A and SERT). Selected compounds had their metabolic stability in a first-pass test (human liver microsomes, NADPH) determined in vitro , and R 1 and R 2 substituents present on the terminal residue of pyrido[ 1 , 2 - c ]pyrimidine were recognized as having an impact on stability.