Structure–activity relationships and molecular studies of novel arylpiperazinylalkyl purine-2,4-diones and purine-2,4,8-triones with antidepressant and anxiolytic-like activity

Arylpiperazinylalkyl derivatives of 8-amino-1,3-dimethylpurine-2,6-dione as novel multitarget 5-HT/D receptor agents with potential antipsychotic activity

“…The protonated nitrogen atom of the arylpiperazine moiety binds to Asp3.32 (charge-reinforced H-bond), while the aryl ring interacts with Phe6.52 (-stacking) and Lys191 (-cation). Binding mode analysis confirmed that substitution of the methoxy group in position 2 of the aryl ring is the most beneficial in the series, since it enables H bonding with Lys191 and does not interfere with other aminoacid residues constituting the binding pocket 59 . The 1,3-dimethylpurine-2,6-dione moiety stabilizes the ligandreceptor complex by -stacking with Tyr2.64, while its substituent in position 8 fills the non-specific cavity below the second extracellular loop (ECL 2).…”

4WD to Travel Inside the 5-HT1A Receptor World

“…In preliminary pharmacological in vivo studies, the selected compound 73 behaves as a potential antidepressant in mice and, at the dose of 2.5 mg/kg, shows anxiolytic effect (Figure 27). Finally, purine 2,4,8-trione derivatives show affinity values lower than those of the corresponding purine 2,4-dione analogues (Figure 27) [41].…”

Synthesis and biological evaluation of 2-fluoro and 3-trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as potential antidepressant agents

“…The inhibition constants K i were determined based on previously described protocols 29,32 . One millimolar stock solutions of the compounds to be tested was prepared in DMSO.…”

“…All the assays were carried out in duplicates (n ¼ 2). The inhibition constants K i for D 2 and 5-HT 2A,6 receptors were determined based on previously described protocols 29,32 .…”

“…Annulated derivatives of theophylline with an LCAP moiety demonstrate high affinity toward serotonin 5-HT 1A and moderate affinity to 5-HT 2A and 5-HT 7 and the dopaminergic D 2 receptor site. Preclinical results indicate that monosubstituted derivatives of LCAPs with an imidazo[2,1-f]purine-2,4-dione as the terminal part act as antipsychotics with additional antidepressant and anxiolytic properties [29][30][31][32] . In view of this and our earlier chemical and pharmacological investigation, in the current study, we designed and synthesized a new series of 2-fluoro and 3-trifluoromethylphenylpiperazinyalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-diones.…”