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Synthesis, structure-activity relationship and biological evaluation of novel arylpiperzines as alpha(1A/1D)-AR subselective antagonists for BPH
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2015 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 23, no 24, 7735-7742 p.Article in journal (Refereed) PublishedText
Abstract [en]

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

Place, publisher, year, edition, pages
Elsevier, 2015. Vol. 23, no 24, 7735-7742 p.
Keyword [en]
alpha(1)-ARs, Subtype selectivity, Arylpiperazine derivatives, Antagonic activity, Homology modeling, Structure-activity relationship
National Category
Biochemistry and Molecular Biology Chemical Sciences
URN: urn:nbn:se:kth:diva-180493DOI: 10.1016/j.bmc.2015.11.020ISI: 000366645600023ScopusID: 2-s2.0-84949723621OAI: diva2:895643

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Available from: 2016-01-19 Created: 2016-01-14 Last updated: 2016-01-19Bibliographically approved

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Sun, Xianqiang
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