Novel Radiolabeled Vanilloid with Enhanced Specificity for Human Transient Receptor Potential Vanilloid 1 (TRPV1)

J Med Chem. 2017 Oct 12;60(19):8246-8252. doi: 10.1021/acs.jmedchem.7b00859. Epub 2017 Sep 21.

Abstract

Transient receptor potential vanilloid 1 (TRPV1) has emerged as a promising therapeutic target. While radiolabeled resiniferatoxin (RTX) has provided a powerful tool for characterization of vanilloid binding to TRPV1, TRPV1 shows 20-fold weaker binding to the human TRPV1 than to the rodent TRPV1. We now describe a tritium radiolabeled synthetic vanilloid antagonist, 1-((2-(4-(methyl-[3H])piperidin-1-yl-4-[3H])-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)urea ([3H]MPOU), that embodies improved absolute affinity for human TRPV1 and improved synthetic accessibility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoxazines / chemical synthesis
  • Benzoxazines / pharmacology*
  • Binding Sites / drug effects
  • Humans
  • Protein Binding
  • Rats
  • Structure-Activity Relationship
  • Substrate Specificity
  • TRPV Cation Channels / drug effects*
  • Urea / analogs & derivatives*
  • Urea / chemical synthesis
  • Urea / pharmacology

Substances

  • 1-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(3-oxo-3,4-dihydro-2H-benzo(b)(1,4)oxazin-8-yl)urea
  • Benzoxazines
  • TRPV Cation Channels
  • TRPV1 protein, human
  • Urea