The design and synthesis of novel, phosphonate-containing transient receptor potential melastatin 8 (TRPM8) antagonists

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2922-6. doi: 10.1016/j.bmcl.2012.02.060. Epub 2012 Feb 27.


A series of benzothiophene-based phosphonates was synthesized and many analogs within the series were shown to be potent antagonists of the TRPM8 channel. The compounds were obtained as a racemic mixture in 5 synthetic steps, and were tested for TRPM8 antagonist activity in a recombinant, canine TRPM8-expressing cell line using a fluorometric imaging plate reader (FLIPR) assay. Structure-activity relationships were developed initially by modification of the core structure and subsequently by variation of the aromatic substituents and the phosphonate ester. Compound 9l was administered intraperitoneally to rats and demonstrated engagement of the TRPM8 target in both prevention and reversal-modes in an icilin-induced 'wet-dog' shake model.

MeSH terms

  • Animals
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Dogs
  • Drug Design*
  • Inhibitory Concentration 50
  • Molecular Structure
  • Organophosphonates / chemical synthesis*
  • Organophosphonates / chemistry
  • Organophosphonates / pharmacology
  • Protein Binding / drug effects
  • Rats
  • Structure-Activity Relationship
  • TRPM Cation Channels / antagonists & inhibitors*


  • Organophosphonates
  • TRPM Cation Channels
  • TRPM8 protein, human