Antidepressant- and anxiolytic-like activity of 7-phenylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 5-HT1A receptor functional profile

作者：Partyka Anna^*; Chlon Rzepa Grazyna; Wasik Anna; Jastrzebska Wiesek Magdalena; Bucki Adam; Kolaczkowski Marcin; Satala Grzegorz; Bojarski Andrzej J; Wesolowska Anna

来源：Bioorganic & Medicinal Chemistry, 2015, 23(1): 212-221.

DOI：10.1016/j.bmc.2014.11.008

• Purine-2,6-diones
• Long-chain arylpiperazines
• Depression
• Anxiety
• 5-HT1A receptor agonist/antagonist
• 5-HT2A receptor antagonist
• 5-HT7 receptor antagonist

Continuing our earlier study in a group of purine-2,6-dione derivatives of long chain arylpiperazines (LCAPs), a series of 8-unsubstituted 7-phenylpiperazin-4-yl-alkyl (4-14) and 7-tetrahydroisoquinolinyl-alkyl (15-17) analogues were synthesized and their serotonin 5-HT1A, 5-HT2A, 5-HT6, 5-HT7 and dopamine D-2 receptor affinities were determined. The study allowed us to identify some potent 5-HT1A receptor ligands with additional moderate affinity for 5-HT2A, 5-HT7 and dopamine D-2 receptors.
Compounds 9, 12, 13 and 14, with the highest 5HT(1A) receptor affinity, were selected for further functional in vivo studies and behavioural evaluation of antidepressant-and antianxiety-like activity. Compounds 9, 12 and 13 showed features of agonists of pre- and/or post-synaptic 5-HT1A receptors, whereas 14 was classified as an antagonist of postsynaptic sites. Moreover, derivatives 9 and 14 acted as antagonists of 5-HT2A receptors. In behavioural studies, compounds 9 and 13 showed antidepressant-like activity in the mouse forced swim test, and their effects were similar or stronger than those of imipramine. Compounds 9, 12 and 14 displayed potential anxiolytic-like properties in the mouse four-plate test, similar or even greater than those of the reference anxiolytic drug, diazepam.

• 出版日期2015-1-1