Arylpiperazinylalkyl derivatives of 8-amino-1,3-dimethylpurine-2,6-dione as novel multitarget 5-HT/D receptor agents with potential antipsychotic activity

作者：Chlon Rzepa Grazyna^*; Bucki Adam; Kolaczkowski Marcin; Partyka Anna; Jastrzebska Wiesek Magdalena; Satala Grzegorz; Bojarski Andrzej J; Kalinowska Tluscik Justyna; Kazek Grzegorz; Mordyl Barbara; Gluch Lutwin Monika; Wesolowska Anna

来源：Journal of Enzyme Inhibition and Medicinal Chemistry, 2016, 31(6): 1048-1062.

DOI：10.3109/14756366.2015.1088844

• Antipsychotics
• arylpiperazines
• D-2 partial agonist
• derotonin receptor ligands

A series of new 7-arylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 8-amino substituent in 8 position was synthesized and their 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, and D-2 receptor affinities were determined. The binding study allowed identifying some potent 5-HT1A/5-HT2A/5-HT7/D-2 ligands. The most interesting because of their multireceptor profile were 8-piperidine (30-35) and 8-dipropylamine (45-47) analogs with four and five carbon aliphatic linkers. The selected compounds 24, 31, 34, 39, 41, 43, 45, and 46 in the functional in vitro evaluation for all targeted receptors showed significant partial D-2 agonist, partial 5-HT1A agonist, and 5-HT2A antagonist properties. The advantageous in vitro affinity of compound 34 for 5-HT1A and D-2 receptors has been explained by means of molecular modeling, taking into consideration its partial agonist activity towards the latter one. In behavioral studies, compounds 32 and 34 revealed antipsychotic-like properties, significantly decreasing D-amphetamine-induced hyperactivity in mice.

• 出版日期2016