Synthesis, computational simulations and biological evaluation of new dual 5HT_1A/5HT₇ receptor ligands based on purine-2,6-dione scaffold

The new dual 5HT_1A/5HT₇ receptor ligands were designed based on the purine-2,6-dione scaffold with the fluorine atom. Twenty-one new derivatives were synthesized, and their structure-activity relationship was summarized. Compound 11 (7-(2-(3-fluorophenyl)-2-oxoethyl)-8-((4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)amino)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione) showed the highest affinity to 5HT_1AR and 5HT₇R, and was the most potent antagonist of 5-HT_1AR (K_b = 0.26 ± 0.1 nM) which activity can be to reference compound NAN-190 (K_b = 0.26 ± 0.1 nM). The experimentally established physicochemical parameters of compound 11 showed that compound, as slightly ionized in the blood, could penetrate the blood-brain barrier. A molecular docking study showed that the fluorine substitution introduces additional stabilization effects on binding to 5HT_1A/5HT₇Rs. In animal assays of depression and anxiety, compound 11 revealed activity in terms of dosage compared to marketed psychotropics such as fluoxetine, citalopram, and sertraline.