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 α1D subtype. Tissue functional assay in vitro showed that compound 2 exerted strong antagonistic activity on α1B-AR (pA2 7.13) with a poor selectivity for α1A and α1D subtypes. Compound 1 exhibited enhanced antagonistic effect on α1D subtype (pA2 7.06) and excellent selectivity for α1D over α1B (α1D/α1B 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 α1D-selective antagonists.
Bioorganic & medicinal chemistry. 2016 Sep 13 [Epub ahead of print]
Wei Xu, Junjun Huang, Binhao Shao, Xingjie Xu, Renwang Jiang, Mu Yuan
School of Pharmaceutical Sciences, Jinan University, Guangzhou 510632, China., Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, China., School of Pharmaceutical Sciences, Jinan University, Guangzhou 510632, China. Electronic address: ., Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, China. Electronic address: .