title: Niclosamide is a Negative Allosteric Modulator of Group I Metabotropic Glutamate Receptors: Implications for Neuropathic Pain.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  To our knowledge, this is the first report of the salicylanilide class of compounds as potential treatments for NP.
authors.affiliation: Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, People's Republic of China.
authors.forename: Ni
authors.initials: N
authors.lastname: Ai
authors.affiliation: Snowdon, Inc., Princeton, New Jersey, 08540, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Wood
authors.affiliation: Snowdon, Inc., Princeton, New Jersey, 08540, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Yang
authors.affiliation: 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. welshwj@rwjms.rutgers.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Welsh
mesh_terms: D000494:Allosteric Regulation; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002460:Cell Line; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D062105:Molecular Docking Simulation; D009437:Neuralgia / Q000188:drug therapy*; D009534:Niclosamide / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000700:Analgesics; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D009534:Niclosamide
keywords: group I metabotropic glutamate receptors; neuropathic pain; niclosamide