Discovery of an enantiopure N-[2-hydroxy-3-phenyl piperazine propyl]-aromatic carboxamide derivative as highly selectiveα_(1D/1A)-adrenoceptor antagonist and homology modelling  

作　　者：Junjun Huang Ran Chen Yajian Huang Hang Zhang Anran Zheng Qing Xiao Dan Wu Ruxia Duan Zhi Zhou Fei He Wei Yi 

机构地区：[1]The Fifth Affiliated Hospital,Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target&Clinical Pharmacology,the NMPA and State Key Laboratory of Respiratory Disease,School of Pharmaceutical Sciences,Guangzhou Medical University,Guangzhou 511436,China [2]Department of Pharmacy,The Third Affiliated Hospital of Guangzhou Medical University,Guangzhou 510150,China [3]School of Traditional Chinese Medicine,Southern Medical University,Guangzhou 510515,China

出　　处：《Chinese Chemical Letters》2024年第11期435-441,共7页中国化学快报（英文版）

基　　金：supported by Natural Science Foundation of Guangdong Province(Nos.2021A1515010101,2021A1515011372,2023A1515011895);National Natural Science Foundation of China(Nos.21807017,82273759,32371529);Guangzhou Medical University Scientific Research Capacity Improvement Project(No.02-410-2405104)。

摘　　要：α_(1)-Adrenergic receptor(AR)blockers can be effective for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms(BPH/LUTS),their usage is limited by cardiovascular-related side effects that are caused by the subtype nonselective nature or low selectivity of many current drugs.We previously reported that phenylpiperazine analogues with amide and propane linker were moderateα_(1D/1A)adrenoceptor antagonists and exhibited better anti-BPH effect than lead compound naftopidil(NAF)in vivo,however,with modestα_(1D/1A)-subtype selectivity.Herein,we replaced propane moiety with2-hydroxypropanol linker and synthesized twenty-seven racemic derivatives with modified aromatic and hetero aromatic groups.Of these new compounds,quinoline surrogate 17 exhibited extremely weak antagonistic affinity onα_(1B)in both cell-based calcium assay and tissue-based functional assay,so that elicited significantα_(1A/1B)andα_(1D/1B)selectivity.Intriguingly,the R enantiomer of 17 preferentially displayed superior anti-BPH effect in rat model compared with S-17,supporting ligand regulates the receptor in a highly stereospecific manner.Finally,the computer-aided modelling research was also performed in order to deeply understand the unique binding mode of R-17 in complex withα_(1A)and the subtype receptor selectivity for R-17 was also rationalized in this study.Taken together,our work enriched the diversity of phenylpiperazines for the treatment of BPH/LUTS,and provided a basis for discovery ofα_(1D/1A)-selective ligands.

关 键 词：Benign prostatic hyperplasia α_(1)-AR antagonist Phenylpiperazine Homology modelling Subtype selectivity 

分 类 号：R914[医药卫生—药物化学]