Potent CaV3.2 channel inhibitors exert analgesic effects in acute and chronic pain models

Peter Muiruri Kamau; Hao Li; Zhihao Yao; Yalan Han; Anna Luo; Hao Zhang; Chantana Boonyarat; Chavi Yenjai; James Mwangi; Lin Zeng; Shilong Yang; Ren Lai; Lei Luo

doi:10.1016/j.biopha.2022.113310

Potent Ca_V3.2 channel inhibitors exert analgesic effects in acute and chronic pain models

Biomed Pharmacother. 2022 Sep:153:113310. doi: 10.1016/j.biopha.2022.113310. Epub 2022 Jun 18.

Authors

Peter Muiruri Kamau¹, Hao Li¹, Zhihao Yao², Yalan Han³, Anna Luo¹, Hao Zhang¹, Chantana Boonyarat⁴, Chavi Yenjai⁵, James Mwangi¹, Lin Zeng³, Shilong Yang⁶, Ren Lai⁷, Lei Luo⁸

Affiliations

¹ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Sino-African Joint Research Center, and Engineering Laboratory of Peptides, Kunming Institute of Zoology, Kunming 650107, Yunnan, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Sino-African Joint Research Center, and Engineering Laboratory of Peptides, Kunming Institute of Zoology, Kunming 650107, Yunnan, China; College of Wildlife and Protected Area, Northeast Forestry University, Harbin 150040, China.
³ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Sino-African Joint Research Center, and Engineering Laboratory of Peptides, Kunming Institute of Zoology, Kunming 650107, Yunnan, China.
⁴ Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.
⁵ Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand.
⁶ College of Wildlife and Protected Area, Northeast Forestry University, Harbin 150040, China.
⁷ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Sino-African Joint Research Center, and Engineering Laboratory of Peptides, Kunming Institute of Zoology, Kunming 650107, Yunnan, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: rlai@mail.kiz.ac.cn.
⁸ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, National Resource Center for Non-Human Primates, Kunming Primate Research Center, National Research Facility for Phenotypic & Genetic Analysis of Model Animals (Primate Facility), Sino-African Joint Research Center, and Engineering Laboratory of Peptides, Kunming Institute of Zoology, Kunming 650107, Yunnan, China. Electronic address: luolei@mail.kiz.ac.cn.

PMID: 35728351
DOI: 10.1016/j.biopha.2022.113310

Abstract

Pain is the most common presenting physical symptom and a primary reason for seeking medical care, which chronically affects people's mental health and social life. Ca_V3.2 channel plays an essential role in the peripheral processing maintenance of pain states. This study was designed to identify novel drug candidates targeting the Ca_V3.2 channel. Whole-cell patch-clamp, cellular thermal shift assay, FlexStation, in vivo and in vitro Ca_V3.2 knock-down, site-directed mutagenesis, and double-mutant cycle analysis were employed to explore the pain-related receptors and ligand-receptor direct interaction. We found that toddaculin efficiently inhibits the Ca_V3.2 channel and significantly reduced the excitability of dorsal root ganglion neurons and pain behaviors. The Carbonyl group of coumarins directly interacts with the pore domain of Ca_V3.2 via van der Waals (VDW) force. Docking with binding pockets further led us to identify glycycoumarin, which exhibited more potent inhibition on the Ca_V3.2 channel and better analgesic activity than the parent compound. Toddaculin and its analog showed beneficial therapeutic effects in pain models. Toddaculin binding pocket on Ca_V3.2 might be a promising docking site for the design of drugs.

Keywords: Analgesic activity; Ca(V)3.2; Drug design; Pain; Toddaculin.

MeSH terms

Analgesics / metabolism
Analgesics / pharmacology
Analgesics / therapeutic use
Calcium Channels, T-Type* / metabolism
Chronic Pain* / drug therapy
Chronic Pain* / metabolism
Ganglia, Spinal / metabolism
Humans
Neurons / metabolism

Substances

Analgesics
Calcium Channels, T-Type