Clobenpropit analogs as dual activity ligands for the histamine H3 and H4 receptors: synthesis, pharmacological evaluation, and cross-target QSAR studies

Bioorg Med Chem. 2009 Jun 1;17(11):3987-94. doi: 10.1016/j.bmc.2009.04.007. Epub 2009 Apr 11.

Abstract

Previous studies have demonstrated that clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) binds to both the human histamine H(3) receptor (H(3)R) and H(4) receptor (H(4)R). In this paper, we describe the synthesis and pharmacological characterization of a series of clobenpropit analogs, which vary in the functional group adjacent to the isothiourea moiety in order to study structural requirements for H(3)R and H(4)R ligands. The compounds show moderate to high affinity for both the human H(3)R and H(4)R. Furthermore, the changes in the functional group attached to the isothiourea moiety modulate the intrinsic activity of the ligands at the H(4)R, ranging from neutral antagonism to full agonism. QSAR models have been generated in order to explain the H(3)R and H(4)R affinities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Histamine H3 Antagonists / chemistry*
  • Histamine H3 Antagonists / pharmacology
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Ligands
  • Male
  • Molecular Structure
  • Protein Binding / drug effects
  • Quantitative Structure-Activity Relationship*
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, Histamine / chemistry*
  • Receptors, Histamine H3 / chemistry*
  • Receptors, Histamine H4
  • Thiourea / analogs & derivatives*
  • Thiourea / chemical synthesis
  • Thiourea / chemistry
  • Thiourea / pharmacology

Substances

  • HRH4 protein, human
  • Histamine H3 Antagonists
  • Imidazoles
  • Ligands
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Receptors, Histamine H3
  • Receptors, Histamine H4
  • Thiourea
  • clobenpropit