Synthesis, structure-activity relationship and biological evaluation of novel arylpiperzines as α_1A/1D-AR subselective antagonists for BPH

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• 作者：Fang Xu^a ; ^&dagger ; ; ^{xufang@jnu.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Hong Chen^b ; ^&dagger ; ; Jingyi Xu^c ; Xue Liang^c ; Xuelan He^c ; Binhao Shao^c ; Xianqiang Sun^d ; Bing Li^e ; Xiaoliang Deng^e ; Mu Yuan^c ; ^{mryuanmu@aliyun.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：α1-ARs ; Subtype selectivity ; Arylpiperazine derivatives ; Antagonic activity ; Homology modeling ; Structure&ndash ; activity relationship
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2015
• 出版时间：15 December 2015
• 年：2015
• 卷：23
• 期：24
• 页码：7735-7742
• 全文大小：1353 K

文摘

A series of novel arylpiperazine derivatives as α_1A/1D-adrenergic receptors (AR) subtype selective antagonists were designed, synthesized and evaluated for their antagonistic activities towards α₁-ARs (α_1A, α_1B, and α_1D). Compounds 9, 12, 13, 15, 17, 18, 21, 22, 25 and 26 exerted strong antagonistic effects on α_1A and/or α_1D subtypes over α_1B in vitro. SAR analysis indicated that chloride at the ortho-phenyl position for compound 17 was beneficial for the highest α_1A/D-AR sub-selectivity. Moreover, molecular docking study of compound 17 with the homology-modeled α₁-ARs (α_1A, α_1B, and α_1D) structures exhibited differences of key amino resides in the docking pocket which may influence the subtype selectivity. ILE 193 of α_1A 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).