Discovery of an enantiopure N -[2-hydroxy-3-phenyl piperazine propyl]-aromatic carboxamide derivative as highly selective α1D/1A-adrenoceptor antagonist and homology modelling

alpha 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 moderate alpha 1D/1A adrenoceptor antagonists and exhibited better anti-BPH effect than lead compound naftopidil (NAF) in vivo , however, with modest alpha 1D/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 antagonistic affinity on alpha 1B in both cell-based calcium assay and tissue-based functional assay, so that elicited significant alpha 1A/1B and alpha 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 with alpha 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 of alpha 1D/1A-selective ligands. (c) 2024 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.