New 7-arylpiperazinylalkyl-8-morpholin-4-yl-purine-2,6-dione derivatives with anxiolytic activity – Synthesis, crystal structure and structure–activity study

Abstract

On the basis of our earlier studies with serotonin (5-HT) receptor ligands in the group of long-chain arylpiperazines (LCAPs), a new series of 7-arylpiperazinylalkyl-8-morpholin-4-yl-purine-2,6-dione derivatives (5–12) has been designed, synthesised and studied in vitro for their affinity for 5-HT1A, 5-HT2A, 5-HT6 and 5-HT7 receptors. The introduction of o-OCH3 and m-Cl into the phenylpiperazinyl moiety as well as the elongation of the linker between purine-2,6-dione core and arylpiperazine fragment modified the affinity for the tested 5-HT receptors. The structures of compounds 9–11 (hydrochloride salts) were confirmed by an X-ray diffraction method. All molecules adopted a different conformation in the crystal. The strongest observed type of interaction is a charge assisted hydrogen bond N+–H⋯Cl−. Additionally, the π–π interactions between 1,3-dimethyl-3,7-dihydropurine-2,6-dione cores of the neighbouring molecules were also observed. As it is observed in the presented crystal structures, the morpholine ring (a potential donor and acceptor of the hydrogen bonds) seems to be an attractive substituent, that may support binding to the non-specific sites of 5-HT receptors. Another interesting feature is the mutual orientation of rings in the arylpiperazine fragment, with plausible influence on ligand-receptor recognition. For compound 10, with strong 5-HT1A binding affinity, the mutual orientation of rings is determined by the intramolecular weak C–H⋯O hydrogen bond. This observation may contribute to a better understanding of the more selective binding of o-OCH3 arylpiperazine derivatives to the 5-HT1A receptor.