Bufotenine and its derivatives: synthesis, analgesic effects identification and computational target prediction

Chao Zhao; Min Chen; Shan-Liang Sun; Jiao-Jiao Wang; Yue Zhong; Huan-Huan Chen; He-Min Li; Han Xu; Nian-Guang Li; Hong-Yue Ma; Xiao-Long Wang

doi:10.1016/S1875-5364(21)60044-4

Bufotenine and its derivatives: synthesis, analgesic effects identification and computational target prediction

Chin J Nat Med. 2021 Jun;19(6):454-463. doi: 10.1016/S1875-5364(21)60044-4.

Authors

Affiliations

¹ National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China.
² National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: linianguang@njucm.edu.cn.
³ National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: hongyuema@njucm.edu.cn.
⁴ National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: gregwang@njucm.edu.cn.

PMID: 34092296
DOI: 10.1016/S1875-5364(21)60044-4

Abstract

Natural product bufotenine (5) which could be isolated from Venenum Bufonis, has been widely used as a tool in central nervous system (CNS) studies. We present here its quaternary ammonium salt (6) which was synthesized with high yields using 5-benzyloxyindole as raw materials, and we firstly discover its analgesic effects in vivo. The analgesic evaluation showed that compounds 5 and 6 had stronger effects on the behavior of formalin induced pain in mice. Moreover, the combination of compound 6 and morphine has a synergistic effect. We intended to explain the molecular mechanism of this effect. Therefore, 36 analgesic-related targets (including 15 G protein-coupled receptors, 6 enzymes, 13 ion channels, and 2 others) were systemically evaluated using reverse docking. The results indicate that bufotenine and its derivatives are closely related to acetyl cholinesterase (AChE) or α₄β₂ nicotinic acetylcholine receptor (nAChR). This study provides practitioners a new insight of analgesic effects.

Keywords: Analgesic; Binding mode; Bufotenine; Reverse docking; Target prediction.

MeSH terms

Analgesics* / pharmacology
Animals
Bufotenin / pharmacology*
Mice
Nicotinic Agonists* / pharmacology
Pain / drug therapy
Receptors, Nicotinic*

Substances

Analgesics
Nicotinic Agonists
Receptors, Nicotinic
Bufotenin