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Niclosamide is a Negative Allosteric Modulator of Group I Metabotropic Glutamate Receptors: Implications for Neuropathic Pain

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Abstract

Purpose

Novel therapeutics are greatly needed that target specific pathological receptors and pathways involved in Neuropathic Pain (NP). Extending our previous work published in this Journal on Group I metabotropic glutamate receptor (mGluR) modulators, we now investigate the therapeutic potential of niclosamide in modulating aberrant glutamate transmission in NP.

Method

Calcium mobilization assays and cross-receptor selectivity experiments are conducted to characterize the pharmacological activity of niclosamide. A focused series of niclosamide analogues is then prepared to elucidate key structural determinants that emerged from computational molecular modeling analysis on drug-receptor interactions. Finally, niclosamide and a carbamate derivative are studied to assess their efficacy in an NP-evoked mechanical hyperalgesia model in rats.

Results

Niclosamide is a low-nanomolar allosteric antagonist of Group I mGluRs with high selectivity for Group I over homologous Group III mGluRs. The phenolic hydroxyl group of niclosamide forms a crucial hydrogen bond with mGluR1/5. Its bioactive coplanar conformation is further stabilized by the nitro substituent on the B ring and an intramolecular bond. Mechanical hyperalgesia in NP rats is reversed by niclosamide through three different dosing routes.

Conclusion

To our knowledge, this is the first report of the salicylanilide class of compounds as potential treatments for NP.

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Abbreviations

CNS:

Central nervous system

IASP:

International Association for the Study of Pain

mGluR:

Metabotropic Glutamate receptor

MPEP:

2-methyl-6-(phenylethynyl)pyridine

NAM:

Negative allosteric modulator

NP:

Neuropathic pain

PAM:

Positive allosteric modulator

PSN:

Partial sciatic nerve

SAM:

Silent allosteric modulator

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors acknowledge the resources, encouragement and support provided by Snowdon, Inc. (Monmouth Junction, NJ, USA). WJW wishes to acknowledge partial support for this work from the National Institutes of Health-National Institute for Environmental Health Sciences [P30 ES005022]. NA wishes to acknowledge partial support for this work from the National Natural Science Foundation of China grant [81520988]. The authors declare that they have no conflict of interests.

Author Contributions

Participated in research design: N. Ai, R.D. Wood, and W.J. Welsh.

Conducted experiments: N. Ai, R.D. Wood, and E. Yang.

Contributed new reagents or analytic tools: R.D. Wood and W.J. Welsh.

Performed data analysis: N. Ai, R.D. Wood, E. Yang, and W.J. Welsh.

Wrote or contributed to the writing of the manuscript: N. Ai and W.J. Welsh.

Author information

Authors and Affiliations

  1. Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, People’s Republic of China

    Ni Ai

  2. Snowdon, Inc., Princeton, New Jersey, 08540, USA

    Richard D. Wood & Eric Yang

  3. Department of Pharmacology, Rutgers-Robert Wood Johnson Medical School, Rutgers University, 661 Hoes Lane West, Staged Research Building (room SRB-124), Piscataway, New Jersey, 08854, USA

    William J. Welsh

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  1. Ni Ai
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Correspondence to William J. Welsh.

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Ai, N., Wood, R.D., Yang, E. et al. Niclosamide is a Negative Allosteric Modulator of Group I Metabotropic Glutamate Receptors: Implications for Neuropathic Pain. Pharm Res 33, 3044–3056 (2016). https://doi.org/10.1007/s11095-016-2027-9

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  • DOI: https://doi.org/10.1007/s11095-016-2027-9

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