Aminoalkyl Derivatives of 8‐Alkoxypurine‐2,6‐diones: Multifunctional 5‐HT 1A /5‐HT 7 Receptor Ligands and PDE Inhibitors with Antidepressant Activity

In the search for potential psychotropic agents, a new series of 3,7‐dimethyl‐ and 1,3‐dimethyl‐8‐alkoxypurine‐2,6‐dione derivatives of arylpiperazines, perhydroisoquinolines, or tetrahydroisoquinolines with flexible alkylene spacers ( 5 – 16 and 21–32 ) were synthesized and evaluated for 5‐HT 1A /5‐HT 7 receptor affinities as well as PDE4B1 and PDE10A inhibitory properties. The 1‐(4‐(4‐(2‐hydroxyphenyl)piperazin‐1‐yl)butyl)‐3,7‐dimethyl‐8‐propoxypurine‐2,6‐dione ( 16 ) and 7‐(2‐hydroxyphenyl)piperazinylalkyl‐1,3‐dimethyl‐8‐ethoxypurine‐2,6‐diones ( 31 and 32 ) as potent dual 5‐HT 1A /5‐HT 7 receptor ligands with antagonistic activity produced an antidepressant‐like effect in the forced swim test in mice. This effect was similar to that produced by citalopram. All the tested compounds were stronger phosphodiesterase isoenzyme inhibitors than theophylline and theobromine. The most potent compounds, 15 and 16 , were characterized by 51 and 52% inhibition, respectively, of PDE4B1 activity at a concentration of 10 −5  M. Concerning the above findings, it may be assumed that the inhibition of PDE4B1 may impact on the signal strength and specificity resulting from antagonism toward the 5‐HT 1 and 5‐HT 7 receptors, especially in the case of compounds 15 and 16 . This dual receptor and enzyme binding mode was analyzed and explained via molecular modeling studies.