title: Synthesis, structure-activity relationship and biological evaluation of novel arylpiperzines as α1A/1D-AR subselective antagonists for BPH.
abstract: 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).
authors.affiliation: Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, 601 West Huangpu Blvd, Guangzhou 510632, People's Republic of China. Electronic address: xufang@jnu.edu.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.affiliation: College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang, Henan 471022, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, People's Republic of China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Xu
authors.affiliation: Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, People's Republic of China.
authors.forename: Xue
authors.initials: X
authors.lastname: Liang
authors.affiliation: Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, People's Republic of China.
authors.forename: Xuelan
authors.initials: X
authors.lastname: He
authors.affiliation: Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, People's Republic of China.
authors.forename: Binhao
authors.initials: B
authors.lastname: Shao
authors.affiliation: Division of Theoretical Chemistry and Biology, School of Biotechnology, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden.
authors.forename: Xianqiang
authors.initials: X
authors.lastname: Sun
authors.affiliation: Experimental Medical Research Center, Guangzhou Medical University, Guangzhou 510182, People's Republic of China.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Experimental Medical Research Center, Guangzhou Medical University, Guangzhou 510182, People's Republic of China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Deng
authors.affiliation: Pharmaceutical Research Center, Guangzhou Medical University, 195# Dongfengxi Road, Guangzhou 510182, People's Republic of China. Electronic address: mryuanmu@aliyun.com.
authors.forename: Mu
authors.initials: M
authors.lastname: Yuan
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D011470:Prostatic Hyperplasia / Q000188:drug therapy / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1
keywords: Antagonic activity; Arylpiperazine derivatives; Homology modeling; Structure–activity relationship; Subtype selectivity; α(1)-ARs