Structure-activity relationships and molecular modeling of the N-(3-pivaloyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)benzyl] thiourea template for TRPV1 antagonism

Bioorg Med Chem Lett. 2012 Jun 1;22(11):3656-60. doi: 10.1016/j.bmcl.2012.04.034. Epub 2012 Apr 13.

Abstract

The structure-activity relationships of N-(3-acyloxy-2-benzylpropyl)-N'-4-[(methylsulfonylamino)benzyl] thioureas, which represent simplified RTX-based vanilloids, were investigated by varying the distances between the four principal pharmacophores and assessing binding and antagonistic activity on rTRPV1. The analysis indicated that a 3-pivaloyloxy-2-benzylpropyl C-region conferred the best potency in binding affinity and antagonism. The molecular modeling of this best template with the tetrameric homology model of rTRPV1 was performed to identify its binding interactions with the receptor.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Molecular Dynamics Simulation*
  • Protein Structure, Tertiary
  • Rats
  • Structure-Activity Relationship
  • TRPV Cation Channels / agonists
  • TRPV Cation Channels / antagonists & inhibitors*
  • TRPV Cation Channels / metabolism
  • Thiourea / chemical synthesis
  • Thiourea / chemistry*

Substances

  • TRPV Cation Channels
  • Trpv1 protein, rat
  • Thiourea