Synthesis of Novel Pyrido[1,2-]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT Receptor Ligands.

Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a-i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine () derivatives were synthesized. The chemical structures of the new compounds were confirmed by H and C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT receptor of all derivatives in the series ( and ) and generally low binding affinities for the SERT protein, with the exception of compounds and . Extended affinity tests for the receptors D, 5-HT, 5-HT and 5-HT were conducted with regard to selected compounds (, , and ). All four compounds demonstrated very high affinities for the D and 5-HT receptors. Compounds and also had high affinities for 5-HT, while and held moderate affinities for this receptor. Compounds and were also tested in vivo to identify their functional activity profiles with regard to the 5-HT receptor, with demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for and .