Abstract
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.
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