Identification of Nitazoxanide as a Group I Metabotropic Glutamate Receptor Negative Modulator for the Treatment of Neuropathic Pain: An In Silico Drug Repositioning Study

Abstract

Purpose

Drug repositioning strategies were employed to explore new therapeutic indications for existing drugs that may exhibit dual negative mGluR1/5 modulating activities as potential treatments for neuropathic pain.

Method

A customized in silico-in vitro-in vivo drug repositioning scheme was assembled and implemented to search available drug libraries for compounds with dual mGluR1/5 antagonistic activities, that were then evaluated using in vitro functional assays and, for validated hits, in an established animal model for neuropathic pain.

Results

Tizoxanide, the primary active metabolite of the FDA approved drug nitazoxanide, fit in silico pharmacophore models constructed for both mGluR1 and mGluR5. Subsequent calcium (Ca++) mobilization functional assays confirmed that tizoxanide exhibited appreciable antagonist activity for both mGluR1 and mGluR5 (IC50 = 1.8 μM and 1.2 μM, respectively). The in vivo efficacy of nitazoxanide administered by intraperitoneal injection was demonstrated in a rat model for neuropathic pain.

Conclusion

The major aim of the present study was to demonstrate the utility of an in silico-in vitro-in vivo drug repositioning protocol to facilitate the repurposing of approved drugs for new therapeutic indications. As an example, this particular investigation successfully identified nitazoxanide and its metabolite tizoxanide as dual mGluR1/5 negative modulators. A key finding is the vital importance for drug screening libraries to include the structures of drug active metabolites, such as those emanating from prodrugs which are estimated to represent 5–7% of marketed drugs.

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Abbreviations

CCDL:

Comprehensive clinical drug library

CNS:

Central nervous system

GPCR:

G-protein coupled receptor

HTS:

High-throughput screening

i.p.:

Intraperitoneal

mGluR:

Metabotropic glutamate receptor

MOE:

Molecular Operating Environment

VCDL:

Virtual clinical drug library

VS:

Virtual screening

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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 NIH-NIEHS P30 ES005022.

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Correspondence to William J. Welsh.

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Ai, N., Wood, R.D. & Welsh, W.J. Identification of Nitazoxanide as a Group I Metabotropic Glutamate Receptor Negative Modulator for the Treatment of Neuropathic Pain: An In Silico Drug Repositioning Study. Pharm Res 32, 2798–2807 (2015). https://doi.org/10.1007/s11095-015-1665-7

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KEY WORDS

  • group I metabotropic glutamate receptor (mGluR)
  • in silico drug repositioning
  • mGluR1
  • mGluR5
  • nitazoxanide