Abstract
On the basis of our earlier studies with the serotonin receptor ligands in the group of 1,3-dimethyl-3,7-dihydropurine-2,6-dione derivatives, a series of new arylpiperazinylalkyl and tetrahydroisoquinolinylalkyl analogs of 8-alkoxy-1,3-dimethyl-3,7-dihydropurine-2,6-dione ( 10– 25) and 1,3-dimethyl-7,9-dihydro-3H-purine-2,6,8-trione ( 26– 30) were synthesized and their 5-HT 1A, 5-HT 2A, and 5-HT 7 receptor affinities were determined. The new compounds 17, 18, 20, and 21 were found to be highly active 5-HT 1A receptor ligands ( K i = 11–19 nM) with diversified affinity for 5-HT 2A receptors ( K i = 15–253 nM). Compounds 12, 13, 15, and 19 were moderately potent 5-HT 2A ligands ( K i = 23–57 nM), whereas 17, 18, 24, and 25 showed distinct affinity for 5-HT 7 receptors ( K i = 51–83 nM). Purine-2,6,8-triones showed weak affinities for 5-HT 1A and 5-HT 7 receptors; among them, 27 and 29 were classified as 5-HT 2A receptor ligands. The selected compounds 17 and 21 were pharmacologically evaluated to determine their functional activities at pre-(hypothermia in mice) and post-(lower lip retraction in rats) synaptic 5-HT 1A receptors. Compound 17 showed features of a potential agonist of pre- and post-synaptic 5-HT 1A receptors, whereas 21 was classified as a potential, weak partial agonist of postsynaptic sites. Last of all, the most interesting compound 17 tested in behavioral models showed potential anxiolytic and antidepressant activities.
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