7-Arylpiperazinylalkyl and 7-tetrahydroisoquinolinylalkyl derivatives of 8-alkoxy-purine-2,6-dione and some of their purine-2,6,8-trione analogs as 5-HT1A, 5-HT2A, and 5-HT7 serotonin receptor ligands

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.