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

Authors
Anna Partyka, Gra?yna Ch?o?-Rzepa, Anna Wasik, Magdalena Jastrz?bska-Wi?sek, Adam Bucki, Marcin Ko?aczkowski, Grzegorz Sata?a, Andrzej J Bojarski, Anna Weso?owska

Lab
Department of Clinical Pharmacy, Jagiellonian University Medical College, Kraków, Poland

Journal
Bioorg. Med. Chem.

Abstract
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 D2 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 D2 receptors. Compounds 9, 12, 13 and 14, with the highest 5HT1A 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.

BIOSEB Instruments Used:
Aron Test or Four Plates Test (LE830)