Synthesis of 3-arylpiperazinylalkylpyrrolo[3,2-d]pyrimidine-2,4-dione derivatives as novel, potent, and selective α1-adrenoceptor ligands

Novel compounds characterized by a pyrrolo[3,2-d]pyrimidine-2,4-dione (PPm) system connected through an alkyl chain to a phenylpiperazine (PPz) residue were designed as structural analogues of the α₁-adrenoceptor (α₁-AR) ligand RN5 (1). In this new series of derivatives an arylpyrrolo moiety has replaced the indole nucleus of RN5. Several structural modifications were performed on the PPm and PPz moieties and the connecting alkyl chain. These compounds were synthesized and tested in radioligand binding experiments where many of them showed interesting binding profiles. Some compounds, including 31, 34, and 36, displayed substantial α₁- AR selectivity with respect to serotoninergic 5-HT_1A and dopaminergic D₁ and D₂ receptors. Two different molecular modeling approaches (pharmacophoric mapping and quantitative structure-affinity relationship analysis) have been applied to rationalize, at a quantitative level, the relationships between affinity toward α₁-ARs and the structure of the studied compounds. Several QSAR models have been reported and described, accounting for the influence of various molecular portions on such affinity data.