Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Naphthylisoquinoline alkaloids, a new structural template inhibitor of Nav1.7 sodium channel

Acta Pharmacologica Sinica volume 44, pages 1768–1776 (2023)Cite this article

Abstract

Voltage-gated sodium channel 1.7 (Nav1.7) remains one of the most promising drug targets for pain relief. In the current study, we conducted a high-throughput screening of natural products in our in-house compound library to discover novel Nav1.7 inhibitors, then characterized their pharmacological properties. We identified 25 naphthylisoquinoline alkaloids (NIQs) from Ancistrocladus tectorius to be a novel type of Nav1.7 channel inhibitors. Their stereostructures including the linkage modes of the naphthalene group at the isoquinoline core were revealed by a comprehensive analysis of HRESIMS, 1D, and 2D NMR spectra as well as ECD spectra and single-crystal X-ray diffraction analysis with Cu Kα radiation. All the NIQs showed inhibitory activities against the Nav1.7 channel stably expressed in HEK293 cells, and the naphthalene ring in the C-7 position displayed a more important role in the inhibitory activity than that in the C-5 site. Among the NIQs tested, compound 2 was the most potent with an IC50 of 0.73 ± 0.03 µM. We demonstrated that compound 2 (3 µM) caused dramatical shift of steady-state slow inactivation toward the hyperpolarizing direction (V1/2 values were changed from −39.54 ± 2.77 mV to −65.53 ± 4.39 mV, which might contribute to the inhibition of compound 2 against the Nav1.7 channel. In acutely isolated dorsal root ganglion (DRG) neurons, compound 2 (10 μM) dramatically suppressed native sodium currents and action potential firing. In the formalin-induced mouse inflammatory pain model, local intraplantar administration of compound 2 (2, 20, 200 nmol) dose-dependently attenuated the nociceptive behaviors. In summary, NIQs represent a new type of Nav1.7 channel inhibitors and may act as structural templates for the following analgesic drug development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Structures of compounds 1–25 isolated from Ancistrocladus tectorius.
Fig. 2: Effects of compound 2 on heterologously expressed Nav1.7 channel.
Fig. 3: The subtype selectivity of compound 2 on Nav channels.
Fig. 4: Effects of compound 2 on the steady-state activation and inactivation of Nav1.7 channel.
Fig. 5: Compound 2 suppressed Nav currents and the action potential firing in DRG neurons.
Fig. 6: Analgesic effects of local injection of compound 2 in formalin-induced mouse inflammatory pain model.

Similar content being viewed by others

References

  1. Catterall WA. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron. 2000;26:13–25.

    Article  CAS  PubMed  Google Scholar 

  2. Melnikova DI, Khotimchenko YS, Magarlamov TY. Addressing the issue of tetrodotoxin targeting. Mar Drugs. 2018;16:1053–61.

    Article  Google Scholar 

  3. Djouhri L, Newton R, Levinson SR, Berry CM, Carruthers B, Lawson SN. Sensory and electrophysiological properties of guinea-pig sensory neurones expressing Nav1.7 (PN1) Na+ channel alpha subunit protein. J Physiol. 2003;546:565–76.

    Article  CAS  PubMed  Google Scholar 

  4. Bosmans F, Swartz KJ. Targeting voltage sensors in sodium channels with spider toxins. Trends Pharmacol Sci. 2010;31:175–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Vetter I, Deuis JR, Mueller A, Israel MR, Starobova H, Zhang A, et al. NaV1.7 as a pain target—from gene to pharmacology. Pharmacol Ther. 2017;172:73–100.

    Article  CAS  PubMed  Google Scholar 

  6. Goodwin G, McMahon SB. The physiological function of different voltage-gated sodium channels in pain. Nat Rev Neurosci. 2021;22:263–74.

    Article  CAS  PubMed  Google Scholar 

  7. Alsaloum M, Higerd GP, Effraim PR, Waxman SG. Status of peripheral sodium channel blockers for non-addictive pain treatment. Nat Rev Neurol. 2020;16:689–705.

    Article  CAS  PubMed  Google Scholar 

  8. Li ZM, Chen LX, Li H. Voltage-gated sodium channels and blockers: an overview and where will they go? Curr Med Sci. 2019;39:863–73.

    Article  CAS  PubMed  Google Scholar 

  9. Mulcahy JV, Pajouhesh H, Beckley JT, Delwig A, Du Bois J, Hunter JC. Challenges and opportunities for therapeutics targeting the voltage-gated sodium channel isoform Nav1.7. J Med Chem. 2019;62:8695–710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kingwell K. Nav1.7 withholds its pain potential. Nat Rev Drug Discov. 2019;18:321–3.

    Google Scholar 

  11. Bringmann G, Zhang G, Olschlager T, Stich A, Wu J, Chatterjee M, et al. Highly selective antiplasmodial naphthylisoquinoline alkaloids from Ancistrocladus tectorius. Phytochemistry. 2013;91:220–8.

    Article  CAS  PubMed  Google Scholar 

  12. Tshitenge DT, Feineis D, Mudogo V, Kaiser M, Brun R, Bringmann G. Antiplasmodial ealapasamines A-C, 'mixed' naphthylisoquinoline dimers from the central african liana Ancistrocladus ealaensis. Sci Rep. 2017;7:5767.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Bringmann G, Seupel R, Feineis D, Xu M, Zhang G, Kaiser M, et al. Antileukemic ancistrobenomine B and related 5,1'-coupled naphthylisoquinoline alkaloids from the Chinese liana Ancistrocladus tectorius. Fitoterapia. 2017;121:76–85.

    Article  CAS  PubMed  Google Scholar 

  14. Seupel R, Hemberger Y, Feineis D, Xu M, Seo EJ, Efferth T, et al. Ancistrocyclinones A and B, unprecedented pentacyclic N,C-coupled naphthylisoquinoline alkaloids, from the Chinese liana Ancistrocladus tectorius. Org Biomol Chem. 2018;16:1581–90.

    Article  CAS  PubMed  Google Scholar 

  15. Tang CP, Yang YP, Zhong Y, Zhong QX, Wu HM, Ye Y. Four new naphthylisoquinoline alkaloids from Ancistrocladus tectorius. J Nat Prod. 2000;63:1384–7.

    Article  CAS  PubMed  Google Scholar 

  16. Li J, Seupel R, Feineis D, Mudogo V, Kaiser M, Brun R, et al. Dioncophyllines C2, D2, and F and related naphthylisoquinoline alkaloids from the Congolese liana Ancistrocladus ileboensis with potent activities against plasmodium falciparum and against multiple myeloma and leukemia cell lines. J Nat Prod. 2017;80:443–58.

    Article  CAS  PubMed  Google Scholar 

  17. Aswathanarayan JB, Vittal RR. In vitro evaluation of antioxidant and antibacterial activities of Rotula aquatica and Ancistrocladus heyneanus. J Pharm Res. 2013;6:313–7.

    CAS  Google Scholar 

  18. Dubuisson D, Dennis SG. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain. 1977;4:161–74.

    Article  CAS  PubMed  Google Scholar 

  19. Tjolsen A, Berge OG, Hunskaar S, Rosland JH, Hole K. The formalin test: an evaluation of the method. Pain. 1992;51:5–17.

    Article  PubMed  Google Scholar 

  20. Abbott FV, Franklin KBJ, Westbrook FR. The formalin test: scoring properties of the first and second phases of the pain response in rats. Pain. 1995;60:91–102.

    Article  PubMed  Google Scholar 

  21. McNamara CR, Mandel BJ, Bautista DM, Siemens J, Deranian KL, Zhao M, et al. TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci USA. 2007;104:13525–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. GBD 2017 DALYs and HALE Collaborator. Global, regional, and national disability-adjusted life-years (DALYs) for 333 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390:1260–344.

    Article  Google Scholar 

  23. Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain. 2012;13:715–24.

    Article  PubMed  Google Scholar 

  24. Yam MF, Loh YC, Tan CS, Khadijah Adam S, Abdul Manan N, Basir R. General pathways of pain sensation and the major neurotransmitters involved in pain regulation. Int J Mol Sci. 2018;19:2164–87.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Yang Y, Wang Y, Li S, Xu Z, Li H, Ma L, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J Med Genet. 2004;41:171–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fertleman CR, Baker MD, Parker KA, Moffatt S, Elmslie FV, Abrahamsen B, et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron. 2006;52:767–74.

    Article  CAS  PubMed  Google Scholar 

  27. Ma RSY, Kayani K, Whyte-Oshodi D, Whyte-Oshodi A, Nachiappan N, Gnanarajah S, et al. Voltage gated sodium channels as therapeutic targets for chronic pain. J Pain Res. 2019;12:2709–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sheets PL, Jarecki BW, Cummins TR. Lidocaine reduces the transition to slow inactivation in Nav1.7 voltage-gated sodium channels. Br J Pharmacol. 2011;164:719–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chevrier P, Vijayaragavan K, Chahine M. Differential modulation of Nav1.7 and Nav1.8 peripheral nerve sodium channels by the local anesthetic lidocaine. Br J Pharmacol. 2004;142:576–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zheng YM, Wang WF, Li YF, Yu Y, Gao ZB. Enhancing inactivation rather than reducing activation of Nav1.7 channels by a clinically effective analgesic CNV1014802. Acta Pharmacol Sin. 2018;39:587–96.

    Article  CAS  PubMed  Google Scholar 

  31. Xing JL, Hu SJ, Xu H, Han S, Wan YH. Subthreshold membrane oscillations underlying integer multiples firing from injured sensory neurons. NeuroReport. 2001;12:1311–3.

    Article  CAS  PubMed  Google Scholar 

  32. Wu Q, Henry JL. Delayed onset of changes in soma action potential genesis in nociceptive A-beta DRG neurons in vivo in a rat model of osteoarthritis. Mol Pain. 2009;5:57.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Niu HL, Liu YN, Xue DQ, Dong LY, Liu HJ, Wang J, et al. Inhibition of Nav1.7 channel by a novel blocker QLS-81 for alleviation of neuropathic pain. Acta Pharmacol Sin. 2021;42:1235–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Huang J, Mis MA, Tanaka B, Adi T, Estacion M, Liu S, et al. A typical changes in DRG neuron excitability and complex pain phenotype associated with a Nav1.7 mutation that massively hyperpolarizes activation. Sci Rep. 2018;8:1811.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Alexandrou AJ, Brown AR, Chapman ML, Estacion M, Turner J, Mis MA, et al. Subtype-selective small molecule inhibitors reveal a fundamental role for Nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release. PLoS One. 2016;11:e0152405.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Kim DM, Nimigean CM. Voltage-gated potassium channels: a structural examination of selectivity and gating. Cold Spring Harb Perspect Biol. 2016;8:a029231.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Cao XH, Byun HS, Chen SR, Cai YQ, Pan HL. Reduction in voltage-gated K+ channel activity in primary sensory neurons in painful diabetic neuropathy: role of brain-derived neurotrophic factor. J Neurochem. 2010;114:1460–75.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Science Fund for Distinguished Young Scholars (grant No. 81825021), the Youth Innovation Promotion Association of the Chinese Academy of Sciences (grant No. 2020284), the Fund of Science and Technology Commission of Shanghai Municipality (grant No. 19431906000), the Key-Area Research and Development Program of Guangdong Province (grant No. 2020B0303070002), High-level New R&D Institute (grant No. 2019B090904008) and High-level Innovative Research Institute (grant No. 2021B0909050003) from Department of Science and Technology of Guangdong Province, Zhongshan Municipal Bureau of Science and Technology, the Lingang Laboratory (LG202103-01-06, LG202103-01-05), and the National Science and Technology Innovation 2030 Major Program (grant No. 2021ZD0200900).

Author information

Author notes

  1. These authors contributed equally: Qiao-qiao Wang, Long Wang

Authors and Affiliations

  1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Qiao-qiao Wang, Chun-ping Tang, Xue-qin Chen, Yue-ming Zheng, Sheng Yao, Zhao-bing Gao & Yang Ye

  2. Natural Product Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Qiao-qiao Wang, Chun-ping Tang, Sheng Yao & Yang Ye

  3. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China

    Qiao-qiao Wang

  4. University of Chinese Academy of Sciences, Beijing, 100049, China

    Qiao-qiao Wang, Yue-ming Zheng, Sheng Yao, Zhao-bing Gao & Yang Ye

  5. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China

    Long Wang, Wen-bo Zhang & Zhao-bing Gao

  6. Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Long Wang, Wen-bo Zhang, Xue-qin Chen, Yue-ming Zheng & Zhao-bing Gao

  7. Zhongshan Institute of Drug Discovery, Institution for Drug Discovery Innovation, Chinese Academy of Science, Zhongshan, 528400, China

    Sheng Yao & Zhao-bing Gao

Authors
  1. Qiao-qiao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Long Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wen-bo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chun-ping Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xue-qin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yue-ming Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sheng Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhao-bing Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yang Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SY, YMZ, ZBG and YY conceived and designed the research; QQW, LW and WBZ performed experiments; QQW and LW analyzed the data; CPT and XQC were in charge of resources and softwares; QQW, LW, YMZ, SY, ZBG and YY wrote and reviewed the manuscript. All authors discussed the study.

Corresponding authors

Correspondence to Yue-ming Zheng, Sheng Yao, Zhao-bing Gao or Yang Ye.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Qq., Wang, L., Zhang, Wb. et al. Naphthylisoquinoline alkaloids, a new structural template inhibitor of Nav1.7 sodium channel. Acta Pharmacol Sin 44, 1768–1776 (2023). https://doi.org/10.1038/s41401-023-01084-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41401-023-01084-9

Keywords

Search

Advanced search

Quick links