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Identification of Nitazoxanide as a Group I Metabotropic Glutamate Receptor Negative Modulator for the Treatment of Neuropathic Pain: An In Silico Drug Repositioning Study
- Source :
- Pharmaceutical Research.
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
Abstract
- 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. 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. 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. 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.
- Subjects :
- Male
Drug
media_common.quotation_subject
Pharmaceutical Science
Pharmacology
Receptors, Metabotropic Glutamate
Approved drug
Rats, Sprague-Dawley
Structure-Activity Relationship
chemistry.chemical_compound
Receptors, Kainic Acid
In vivo
medicine
Animals
Computer Simulation
Pharmacology (medical)
Active metabolite
Pain Measurement
media_common
business.industry
Organic Chemistry
Drug Repositioning
Computational Biology
Nitazoxanide
Prodrug
Nitro Compounds
Tizoxanide
High-Throughput Screening Assays
Rats
Thiazoles
Drug repositioning
chemistry
Neuralgia
Molecular Medicine
Sciatic Neuropathy
business
Excitatory Amino Acid Antagonists
Biotechnology
medicine.drug
Subjects
Details
- ISSN :
- 1573904X and 07248741
- Database :
- OpenAIRE
- Journal :
- Pharmaceutical Research
- Accession number :
- edsair.doi.dedup.....79cdb1d61f23403727fbe65245e1c5b4