Citation: Hui Chen, Xieraili Tuerxun, Amina Abula, Yenan Sun, Hanqi Zhang, Guangmin Yao, Haji Akber Aisa. Discovery of pyrethalkalines A and B as potent analgesics with unprecedented chemical skeletons dual targeting TRPM8 and Kv1.2 ion channels[J]. Chinese Chemical Letters, ;2026, 37(4): 111938. doi: 10.1016/j.cclet.2025.111938 shu

Discovery of pyrethalkalines A and B as potent analgesics with unprecedented chemical skeletons dual targeting TRPM8 and Kv1.2 ion channels

Hui Chen ^a ,
Xieraili Tuerxun ^b ,
Amina Abula ^a ,
Yenan Sun ^c ,
Hanqi Zhang ^c ,
Guangmin Yao ^{a, b, c, *,} ,
Haji Akber Aisa ^{a, b, *,}

a.
State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China
b.
The Xinjiang Key Laboratory of Natural Medicine Active Components and Drug Release Technology, Pharmacy College of Xinjiang Medical University, Urumqi 830011, China
c.
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

gyap@mail.hust.edu.cn

haji@ms.xjb.ac.cn

Received Date: 4 August 2025
Revised Date: 1 October 2025
Accepted Date: 9 October 2025
Available Online: 10 October 2025

Figures(5)

Two pairs of potent analgesic alkaloid enantiomers with unprecedented chemical architectures, named pyrethalkalines A (1) and B (2), were isolated from the roots of Anacyclus pyrethrum. Pyrethalkaline A (1) is an unprecedented 6/6/6/6/5-fused pentacyclic triamino alkaloid featuring a unique 8,15-diaza-pentacyclo[12.3.1.1^1,9.0^5,19.0^10,14]nonadecane core, and pyrethalkaline B (2) is a novel 6/6/6/6/5/6-fused hexacyclic triamino alkaloid possessing an unprecedented 8,13,19-triazahexacyclo[16.3.1.1^1,9.0^5,23.0^10,18.0^11,16]tricosane motif. Their structures were elucidated by comprehensive spectroscopic data analysis, quantum ¹³C nuclear magnetic resonance (NMR) DP4+ and electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis, and their plausible biosynthetic pathways were proposed. Alkaloids (±)-1 and (−)-1 at three lower doses of 1, 0.2, and 0.04 mg/kg, and (+)-2 at two lower doses of 1 and 0.2 mg/kg showed more potent analgesic activity than the positive control morphine. Further investigation revealed that (+)-1 and (−)-1 are dual transient receptor potential melastatin 8 (TRPM8) (half-maximal inhibitory concentration (IC₅₀) = 1.90 ± 0.09 and 1.40 ± 0.17 µmol/L, respectively) and Kv1.2 inhibitors. Molecular dockings of 1 provide a novel structural model to develop potent analgesics dual targeting TRPM8 and Kv1.2 ion channels, and (±)-1 have the potential for the development of a non-opioid potent analgesic to treat neurogenic pains.
- Analgesics,
- Alkaloids,
- Dual TRPM8 and Kv1.2 inhibitors,
- Natural products,
- Structural elucidation
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