Design, synthesis, crystal structure, biological evaluation and molecular docking studies of carbazole-arylpiperazine...

Subtype-selective α₁-adrenoceptor (AR) antagonists display optimum therapeutic efficacies for the treatment of benign prostatic hyperplasia (BPH). In this study, we designed and synthesized novel carbazole-arylpiperazines derivatives (1 and 2) on the basis of the proposed pharmacophore model for α₁-AR antagonists. Structural properties were investigated using single-crystal X-ray diffraction analysis. Comparison of crystal structures with ligand-based pharmacophore models revealed that the two agents may possess antagonistic effects on α_1D subtype. Tissue functional assay in vitro showed that compound 2 exerted strong antagonistic activity on α_1B-AR (pA₂ 7.13) with a poor selectivity for α_1A and α_1D subtypes. Compound 1 exhibited enhanced antagonistic effect on α_1D subtype (pA₂ 7.06) and excellent selectivity for α_1D over α_1B (α_1D/α_1B ratio=79.4). To illustrate the relationship between antagonistic activity and chemical structure, molecular docking studies were performed using the homology models of α₁ receptors. Binding mechanism indicated that small hydrophobic substituents attached to the arylpiperazine moiety were essential for rational design of α_1D-selective antagonists.