首页|Discovery of an enantiopure N-[2-hydroxy-3-phenyl piperazine propyl]-aromatic carboxamide derivative as highly selectiveα1D/1A-adrenoceptor antagonist and homology modelling
Discovery of an enantiopure N-[2-hydroxy-3-phenyl piperazine propyl]-aromatic carboxamide derivative as highly selectiveα1D/1A-adrenoceptor antagonist and homology modelling
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α1-Adrenergic receptor(AR)blockers can be effective for the treatment of benign prostatic hyperpla-sia/lower urinary tract symptoms(BPH/LUTS),their usage is limited by cardiovascular-related side ef-fects 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 moder-ate α1D/1A adrenoceptor antagonists and exhibited better anti-BPH effect than lead compound naftopidil(NAF)in vivo,however,with modest α1D/1A-subtype selectivity.Herein,we replaced propane moiety with 2-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 an-tagonistic affinity on α1B in both cell-based calcium assay and tissue-based functional assay,so that elicited significant α1A/1B and α1D/1B selectivity.Intriguingly,the R enantiomer of 17 preferentially dis-played 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 with α 1A and the subtype recep-tor 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 of α1D/1A-selective ligands.
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
Department of Pharmacy,The Third Affiliated Hospital of Guangzhou Medical University,Guangzhou 510150,China
School of Traditional Chinese Medicine,Southern Medical University,Guangzhou 510515,China
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