Synthesis and structural and pharmacological properties of cyclopropane-based conformationally restricted analogs of 4-methylhistamine as histamine H3/H4 receptor ligands

Bioorg Med Chem. 2010 Feb;18(3):1076-82. doi: 10.1016/j.bmc.2009.12.046. Epub 2009 Dec 23.

Abstract

On the basis of the previous results on a histamine H(4) receptor agonist 4-methylhistamine and a cyclopropane-based conformationally restricted analog CEIC (3) with potent H(3)/H(4) receptor antagonistic effect, 4-methylhistamine analogs 4 and 5 of CEIC were designed and synthesized. Compound 4 showed strong affinity (K(i)=38.7 nM) for the H(3) receptor, which was more potent than a well-known H(3) antagonist thioperamide. Stable tautomer and conformation of 3 and 4, which can affect the pharmacological activity, were analyzed by ab initio calculations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclopropanes / chemical synthesis
  • Cyclopropanes / chemistry*
  • Cyclopropanes / pharmacology*
  • Humans
  • Methylhistamines / chemical synthesis
  • Methylhistamines / chemistry*
  • Methylhistamines / pharmacology*
  • Molecular Conformation
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Histamine / metabolism*
  • Receptors, Histamine H3 / metabolism*
  • Receptors, Histamine H4
  • Structure-Activity Relationship

Substances

  • Cyclopropanes
  • HRH4 protein, human
  • Methylhistamines
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Receptors, Histamine H3
  • Receptors, Histamine H4
  • 4-methylhistamine
  • cyclopropane