Reversal of subtype-selectivity and function by the introduction of a para-benzamidyl substituent to N-cyclopropylmethyl nornepenthone

Linghui Kong; Kuan Ning; Xiao Liu; Jiashuo Lu; Baiyu Chen; Rongrong Ye; Zixiang Li; Shuang Jiang; Siyuan Tang; Jing-Rui Chai; Yun Fang; Yingjie Lan; Xiaobo Mai; Qiong Xie; Jinggen Liu; Liming Shao; Wei Fu; Yujun Wang; Wei Li

doi:10.1016/j.ejmech.2023.115589

Reversal of subtype-selectivity and function by the introduction of a para-benzamidyl substituent to N-cyclopropylmethyl nornepenthone

Eur J Med Chem. 2023 Oct 5:258:115589. doi: 10.1016/j.ejmech.2023.115589. Epub 2023 Jun 28.

Authors

Linghui Kong¹, Kuan Ning², Xiao Liu¹, Jiashuo Lu³, Baiyu Chen¹, Rongrong Ye⁴, Zixiang Li¹, Shuang Jiang², Siyuan Tang¹, Jing-Rui Chai⁵, Yun Fang¹, Yingjie Lan¹, Xiaobo Mai¹, Qiong Xie¹, Jinggen Liu⁶, Liming Shao⁷, Wei Fu¹, Yujun Wang⁸, Wei Li⁹

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China.
² School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China.
³ Department of Pharmacy, Dalian Medical University, Dalian, 116044, China.
⁴ CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China; School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai, 201418, China.
⁵ CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China.
⁶ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China. Electronic address: jgliu@simm.ac.cn.
⁷ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China; State Key Laboratory of Medical Neurobiology, Fudan University, No. 138 Yixueyuan Road, Shanghai, 200032, China. Electronic address: limingshao@fudan.edu.cn.
⁸ CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China. Electronic address: yjwang@simm.ac.cn.
⁹ Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China. Electronic address: wei-li@fudan.edu.cn.

PMID: 37413884
DOI: 10.1016/j.ejmech.2023.115589

Abstract

The discovery and development of novel μ-opioid receptor (MOR) antagonists is a significant area to combat Opioid Use Disorder (OUD). In this work, a series of para-substituted N-cyclopropylmethyl-nornepenthone derivatives were designed and synthesized and pharmacologically assayed. Compound 6a was identified as a selective MOR antagonist both in vitro and in vivo. Its molecular basis was elucidated using molecular docking and MD simulations. A subpocket on the extracellular side of the TM2 domain of MOR, in particular the residue Y^2.64, was proposed to be responsible for the reversal of subtype selectivity and functional reversal of this compound.

Keywords: Functional reversal; MOR antagonist; N-cyclopropylmethyl nornepenthone derivatives; Opioid use disorder; Reversal of subtype-selectivity; Structure-activity relationship.

MeSH terms

Ligands
Molecular Docking Simulation
Morphinans* / chemistry
Narcotic Antagonists / pharmacology
Receptors, Opioid, mu
Structure-Activity Relationship

Substances

Morphinans
Ligands
Receptors, Opioid, mu
Narcotic Antagonists