Design, synthesis and biological evaluation of N-hydroxy-aminobenzyloxyarylamide analogues as novel selective κ opioid receptor antagonists

Guangchao He; Qiao Song; Junwei Wang; Anhua Xu; Kewen Peng; Qihua Zhu; Yungen Xu

doi:10.1016/j.bmcl.2020.127236

Design, synthesis and biological evaluation of N-hydroxy-aminobenzyloxyarylamide analogues as novel selective κ opioid receptor antagonists

Bioorg Med Chem Lett. 2020 Jul 1;30(13):127236. doi: 10.1016/j.bmcl.2020.127236. Epub 2020 May 1.

Authors

Guangchao He¹, Qiao Song¹, Junwei Wang¹, Anhua Xu¹, Kewen Peng¹, Qihua Zhu², Yungen Xu³

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
² Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zhuqihua@vip.126.com.
³ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xu_yungen@hotmail.com.

PMID: 32386980
DOI: 10.1016/j.bmcl.2020.127236

Abstract

Aminobenzyloxyarylamide derivatives 1a-i and 2a-t were designed and synthesized as novel selective κ opioid receptor (KOR) antagonists. The benzoyl amide moiety of LY2456302 was changed into N-hydroxybenzamide and benzisoxazole-3(2H)-one to investigate whether it could increase the binding affinity or selectivity for KOR. All target compounds were evaluated in radioligand binding assays for opioid receptor binding affinity. These efforts led to the identification of compound 1c (κ K_i = 179.9 nM), which exhibited high affinity for KOR. Moreover, the selectivity of KOR over MOR and DOR increased nearly 2-fold and 7-fold, respectively, compared with (±)LY2456302.

Keywords: LY2456302; N-hydroxy-aminobenzyloxyarylamide antagonists; Novel; Selective; κ opioid receptor.

MeSH terms

Animals
Benzamides / chemical synthesis
Benzamides / metabolism
Benzamides / pharmacology*
CHO Cells
Cricetulus
Drug Design
HEK293 Cells
Humans
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / metabolism
Hydroxamic Acids / pharmacology*
Molecular Docking Simulation
Narcotic Antagonists / chemical synthesis
Narcotic Antagonists / metabolism
Narcotic Antagonists / pharmacology*
Receptors, Opioid, kappa / metabolism*

Substances

Benzamides
Hydroxamic Acids
Narcotic Antagonists
Receptors, Opioid, kappa