Citation: Junjun Huang, Ran Chen, Yajian Huang, Hang Zhang, Anran Zheng, Qing Xiao, Dan Wu, Ruxia Duan, Zhi Zhou, Fei He, Wei Yi. Discovery of an enantiopure N-[2-hydroxy-3-phenyl piperazine propyl]-aromatic carboxamide derivative as highly selective α_1D/1A-adrenoceptor antagonist and homology modelling[J]. Chinese Chemical Letters, ;2024, 35(11): 109594. doi: 10.1016/j.cclet.2024.109594 shu

Discovery of an enantiopure N-[2-hydroxy-3-phenyl piperazine propyl]-aromatic carboxamide derivative as highly selective α_1D/1A-adrenoceptor antagonist and homology modelling

Junjun Huang ^{a, 1, *,} ,
Ran Chen ^{a, 1} ,
Yajian Huang ^{b, 1} ,
Hang Zhang ^c ,
Anran Zheng ^a ,
Qing Xiao ^a ,
Dan Wu ^a ,
Ruxia Duan ^a ,
Zhi Zhou ^a ,
Fei He ^{c, *,} ,
Wei Yi ^{a, *,}

a.
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
b.
Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China
c.
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China

huangjunjun1985@gzhmu.edu.cn

hefei8131@smu.edu.cn

yiwei@gzhmu.edu.cn

Received Date: 5 December 2023
Revised Date: 26 January 2024
Accepted Date: 29 January 2024
Available Online: 8 February 2024

Figures(5)

α₁-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 α_1D/1A adrenoceptor antagonists and exhibited better anti-BPH effect than lead compound naftopidil (NAF) in vivo, however, with modest α_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 α_1B in both cell-based calcium assay and tissue-based functional assay, so that elicited significant α_1A/1B and α_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 α_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 α_1D/1A-selective ligands.
- Benign prostatic hyperplasia,
- α₁-AR antagonist,
- Phenylpiperazine,
- Homology modelling,
- Subtype selectivity
1. [1]
  R.C. Langan, Urology 46 (2019) 223–232.
2. [2]
  S. Madersbacher, N. Sampson, Z. Culig, Gerontology 65 (2019) 458–464. doi: 10.1159/000496289
3. [3]
  B.M. Launer, K.T. McVary, W.A. Ricke, G.L. Lloyd, BJU Int. 127 (2021) 722–728. doi: 10.1111/bju.15286
4. [4]
  B. Chughtai, J.C. Forde, D.D.M. Thomas, et al., Nat. Rev. Dis. Primer 2 (2016) 16031. doi: 10.1038/nrdp.2016.31
5. [5]
  D.T. Price, D.A. Schwinn, J.W. Lomasney, et al., J. Urol. 150 (1993) 546–551. doi: 10.1016/s0022-5347(17)35544-1
6. [6]
  M. Yoshida, J. Kudoh, Y. Homma, et al., Clin. Interv. Aging 6 (2011) 161–172.
7. [7]
  J.R. Docherty, Eur. J. Pharmacol. 855 (2019) 305–320. doi: 10.1016/j.ejphar.2019.04.047
8. [8]
  G. Chiu, P.J. Connolly, S.A. Middleton, et al., Expert Opin. Ther. Pat. 18 (2008) 1351–1360. doi: 10.1517/13543770802571659
9. [9]
  D. Guo, J. Li, H. Lin, et al., J. Med. Chem. 59 (2016) 9489–9502. doi: 10.1021/acs.jmedchem.6b01217
10. [10]
  F. Zhao, J. Li, Y. Chen, et al., J. Med. Chem. 59 (2016) 3826–3839. doi: 10.1021/acs.jmedchem.5b02023
11. [11]
  M. Pallavicini, R. Budriesi, L. Fumagalli, et al., J. Med. Chem. 49 (2006) 7140–7149. doi: 10.1021/jm060358r
12. [12]
  R. Takei, I. Ikegaki, K. Shibata, et al., Jpn. J. Pharmacol. 79 (1999) 447–454. doi: 10.1254/jjp.79.447
13. [13]
  J.J. Huang, Y. Cai, Y.Z. Yi, et al., Eur. J. Pharmacol. 791 (2016) 473–481. doi: 10.1016/j.ejphar.2016.09.009
14. [14]
  J. Huang, F. He, M. Huang, Eur. J. Med. Chem. 96 (2015) 83–91. doi: 10.1016/j.ejmech.2015.04.005
15. [15]
  J.J. Huang, Z.H. Zhang, F. He, et al., Bioorg. Med. Chem. Lett. 28 (2018) 547–551. doi: 10.1016/j.bmcl.2018.01.068
16. [16]
  Q. Xiao, Q.M. Liu, R.C. Jiang, et al., Front. Pharmacol. 11 (2021) 594038. doi: 10.3389/fphar.2020.594038
17. [17]
  Q. Liu, Q. Xiao, X. Zhu, et al., Eur. J. Pharmacol. 870 (2020) 172817. doi: 10.1016/j.ejphar.2019.172817
18. [18]
  G.H. Kuo, C. Prouty, W.V. Murray, et al., J. Med. Chem. 43 (2000) 2183–2195. doi: 10.1021/jm9905918
19. [19]
  M. Deluigi, L. Morstein, M. Schuster, et al., Nat. Commun. 13 (2022) 382. doi: 10.1038/s41467-021-27911-3
20. [20]
  H. Fang, M.Y. Li, L. Xia, Chin. Chem. Lett. 18 (2007) 41–44.
21. [21]
  E.S. Stoddart, S. Senadheera, I.J.A. MacDougall, et al., PLoS One 6 (2011) e19695. doi: 10.1371/journal.pone.0019695
22. [22]
  L. Fumagalli, M. Pallavicini, R. Budriesi, et al., J. Med. Chem. 56 (2013) 6402–6412. doi: 10.1021/jm400867d
23. [23]
  X. Zhao, M. Yuan, B. Huang, et al., J. Mol. Graph. Model. 29 (2010) 126–136. doi: 10.1016/j.jmgm.2010.05.002
24. [24]
  A.J. Noble, R. Chess-Williams, C. Couldwell, et al., Br. J. Pharmacol. 120 (1997) 231–238. doi: 10.1038/sj.bjp.0700907
25. [25]
  C. Hosoda, A. Tanoue, M. Shibano, et al., Br. J. Pharmacol. 146 (2005) 456–466. doi: 10.1038/sj.bjp.0706325
26. [26]
  S.W. Seto, S. Bexis, P.A. McCormick, et al., Eur. J. Pharmacol. 644 (2010) 113–119. doi: 10.1016/j.ejphar.2010.06.035
27. [27]
  M.T. Quiles, M.A. Arbós, A. Fraga, et al., Prostate 70 (2010) 1044–1053. doi: 10.1002/pros.21138
28. [28]
  N.G. Bahey, E.A.E. El-Drieny, J. Microsc. Ultrastruct. 3 (2015) 75–81. doi: 10.1016/j.jmau.2015.01.002
29. [29]
  R. Barbaro, L. Betti, M. Botta, et al., J. Med. Chem. 44 (2001) 2118–2132. doi: 10.1021/jm010821u
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沈阳化工大学材料科学与工程学院沈阳 110142

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

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通讯作者: 陈斌, bchen63@163.com

Discovery of an enantiopure N-[2-hydroxy-3-phenyl piperazine propyl]-aromatic carboxamide derivative as highly selective α_1D/1A-adrenoceptor antagonist and homology modelling