New Arylpiperazinylalkyl Derivatives of 8-Alkoxy-purine-2,6-dione and Dihydro[1,3] oxazolo[2,3-f] purinedione Targeting the Serotonin 5-HT1A/5-HT2A/5-HT7 and Dopamine D2 Receptors

To obtain potential antidepressants and/or antipsychotics, a series of new long-chain arylpiperazine derivatives of 8-alkoxy-purine-2,6-dione (10-24) and dihydro[1,3]oxazolo[2,3-f]purinedione (30-34) were synthesized and their serotonin (5-HT1A, 5-HT2A, 5-HT6, 5-HT7) and dopamine (D-2) receptor affinities were determined. The study allowed the identification of some potent 5-HT1A/5-HT7/D-2 ligands with moderate affinity for 5-HT2A sites. The binding mode of representative compounds from both chemical classes (11 and 31) in the site of 5-HT1A receptor was analyzed in computational studies. In functional in vitro studies, the selected compounds 15 and 16 showed antagonistic properties for the evaluated receptors. 8-Methoxy-7-{4-[4-(2-methoxyphenyl)-piperazin-1-yl]-butyl}-1,3-dimethyl-purine-2,6-dione (15) showed a lack of activity in terms and under the conditions of the forced swim, four plate and amphetamine-induced hyperactivity tests in mice, probably as a result of its high first pass effect in the liver.