The roots ofAnacyclus pyrethrum, known as A-Na-Qi-Gen in Chinese, are used as a Traditional Chinese Medicine, especially in Xinjiang Uygur Autonomous Region, to treatheadache, migraine headache and cold-type toothache. Neuropathic and cancer-related types, poses significant clinical challenges due to its detrimental effects on mental health, immunity, and survival. Multi-target analgesics with minimal side effects and high efficacy are a key research focus in addressing the global pain crisis.

Prof. Haji Akber AISA′ lab at the Xinjiang Technical Institute of Physics and Chemistry of Chinese Academy of Science and his collaborators isolated 5 pairs of potent analgesic alkaloid enantiomers from the roots of A. pyrethrum using molecular network technology. This work was published in Acta Pharmaceutica Sinica B (IF=14.8, doi.org/10.1016/j.apsb.2025.04.032).

In this study, five pairs of potent analgesic alkaloid enantiomerswere isolated. Their structures were elucidated by comprehensive spectroscopic data analysis, quantum ¹³C NMR, DP4+ and ECD calculations, and single-crystal X-ray diffraction analysis.Anacyphrethines A (1) and B (2) are highly conjugated and polymethylated 6/6/6/6/5/7/5/5-fused octacyclic tetraazabic alkaloids possessing an unprecedented 8,14,18,24-tetraaza-octacyclo[16.8.2.1^1,23.0^4,28.0^5,17.0^9,16.0^11,15.0^21,27] nonacosane motif. Their biosynthetic pathways are proposed involving key aldol, hydroamination, and Schiff base reactions. All compounds showed potent analgesic effectsin vivo.Further tests on 44 analgesic-related targets demonstrated that (+)-1showed significant inhibitory effects against many ion channels such as TRPM8, Kv1.2, Kv1.3, and Ca_v2.1 with IC₅₀values of 1.10 ± 0.26, 4.20 ± 0.07, 2.20 ± 0.24, and 10.40 ± 0.69μM, respectively, while (−)-1primarily inhibited TRPC6, Kv1.2, and Kv1.3 ion channels with IC₅₀values of 0.81 ± 0.05, 0.91 ± 0.04, and 1.50 ± 0.13μM, respectively, without affecting the opioid receptors,suggesting their non-addictive potentials.

This work was supported by the National Key R&D Program of China, the Biological Resources Program, Chinese Academy of Sciences, National Natural Science Foundation of China, Interdisciplinary Research Program of HUST, and International Cooperation Project of Hubei provincial key R&D plan.

Figure: Anacyphrethines A (1) has been demonstrated to exert analgesic effects by targeting multiple non-opioid ion channels. (Image by Prof. Haji Akber AISA′ group)