Synthesis of Novel Pyrido[1,2- c ]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT 1A 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 ( 7a-i ) derivatives were synthesized. The chemical structures of the new compounds were confirmed by 1 H and 13 C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT 1A 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 1A receptor of all derivatives in the series ( 6a-i and 7a-i ) and generally low binding affinities for the SERT protein, with the exception of compounds 6a and 7g . Extended affinity tests for the receptors D 2 , 5-HT 2A , 5-HT 6 and 5-HT 7 were conducted with regard to selected compounds ( 6a , 7g , 6d and 7i ). All four compounds demonstrated very high affinities for the D 2 and 5-HT 2A receptors. Compounds 6a and 7g also had high affinities for 5-HT 7 , while 6d and 7i held moderate affinities for this receptor. Compounds 6a and 7g were also tested in vivo to identify their functional activity profiles with regard to the 5-HT 1A receptor, with 6a demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for 6a and 6d .