Synthesis of new hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives with an arylpiperazine moiety as ligands for 5-HT1A and 5-HT2A receptors. Part 4

New 4-aryl-2H-pyrido[1,2-c]pyrimidine-1,3-dione derivatives of arylpiperazine (6–18) were prepared and evaluated in vitro for their affinity for 5-HT1A, 5-HT2A, and α1 receptors. The influence of ortho substitution in the phenyl ring, substitution at position 4 of the pyrido[1,2-c]pyrimidine system, and its unsaturation degree were explored. The tested compounds showed high affinity for the 5-HT1A receptor (Ki = 1.3–79.2 nM) and moderate to low affinity for the 5-HT2A (Ki = 51.7–1405 nM) and α1 receptors (Ki = 19.7–382.3 nM). Compounds 8 and 10 showed the highest 5-HT1A receptor affinity (Ki = 1.3 and 2.2 nM, respectively) and were 37- and 35.9-fold, respectively, more selective in relation to α1 adrenoreceptors.

Graphical abstractThe synthesis and biological activity of a novel series of 4-aryl-2H-pyrido[1,2-c]pyrimidine-1,3-dione derivatives 6-18 with potent binding affinity for 5-HT1A receptor are reported.Figure optionsDownload full-size imageDownload as PowerPoint slide