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

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

  • Biomed Pharmacother. 2022 Sep;153:113310. doi: 10.1016/j.biopha.2022.113310.
Peter Muiruri Kamau 1,  Hao Li 1,  Zhihao Yao 2,  Yalan Han 3,  Anna Luo 1,  Hao Zhang 1,  Chantana Boonyarat 4,  Chavi Yenjai 5,  James Mwangi 1,  Lin Zeng 3,  Shilong Yang 6,  Ren Lai 7,  Lei Luo 8
Affiliations

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: [email protected].
  • 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: [email protected].
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. CaV3.2 channel plays an essential role in the peripheral processing maintenance of pain states. This study was designed to identify novel drug candidates targeting the CaV3.2 channel. Whole-cell patch-clamp, cellular thermal shift assay, FlexStation, in vivo and in vitro CaV3.2 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 CaV3.2 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 CaV3.2 via van der Waals (VDW) force. Docking with binding pockets further led us to identify glycycoumarin, which exhibited more potent inhibition on the CaV3.2 channel and better analgesic activity than the parent compound. Toddaculin and its analog showed beneficial therapeutic effects in pain models. Toddaculin binding pocket on CaV3.2 might be a promising docking site for the design of drugs.

Keywords

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

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