A series of novel arylpiperazine derivatives as α1A/1D-adrenergic receptors (AR) subtype selective antagonists were designed, synthesized and evaluated for their antagonistic activities towards α1-ARs (α1A, α1B, and α1D).
Compounds 9, 12, 13, 15, 17, 18, 21, 22, 25 and 26 exerted strong antagonistic effects on α1A and/or α1D subtypes over α1B in vitro. SAR analysis indicated that chloride at the ortho-phenyl position for compound 17 was beneficial for the highest α1A/D-AR sub-selectivity. Moreover, molecular docking study of compound 17 with the homology-modeled α1-ARs (α1A, α1B, and α1D) structures exhibited differences of key amino resides in the docking pocket which may influence the subtype selectivity. ILE 193 of α1A was validated as the key residues for binding ligand. This work provides useful information for finding more new potential drugs in clinic in treating benign prostatic hyperplasia (BPH).
Bioorganic & medicinal chemistry. 2015 Nov 19 [Epub]
Fang Xu, Hong Chen, Jingyi Xu, Xue Liang, Xuelan He, Binhao Shao, Xianqiang Sun, Bing Li, Xiaoliang Deng, Mu Yuan
Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, 601 West Huangpu Blvd, Guangzhou 510632, People's Republic of China. College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang, Henan 471022, People's Republic of China. , Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, People's Republic of China. , Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, People's Republic of China. , Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, People's Republic of China. , Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, People's Republic of China. , Division of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden. , Experimental Medical Research Center, Guangzhou Medical University, Guangzhou 510182, People's Republic of China. , Experimental Medical Research Center, Guangzhou Medical University, Guangzhou 510182, People's Republic of China. , Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, People's Republic of China.