N(G)-acylated imidazolylpropylguanidines as potent histamine H4 receptor agonists: selectivity by variation of the N(G)-substituent

J Med Chem. 2009 Apr 23;52(8):2623-7. doi: 10.1021/jm9000693.

Abstract

3-(1H-Imidazol-4-yl)propylguanidine (SK&F 91486, 4) was identified as a potent partial agonist at the human histamine H(3) receptor (hH(3)R) and human histamine H(4) receptor (hH(4)R). With the aim to increase selectivity for the hH(4)R, the guanidine group in 4 was acylated. N(1)-Acetyl-N(2)-[3-(1H-imidazol-4-yl)propyl]guanidine (UR-PI288, 13) was a potent full agonist at the hH(4)R (pEC(50) = 8.31; alpha = 1.00), possessing more than 1000- and 100-fold selectivity relative to the hH(1)R and hH(2)R, respectively, and possessing only low intrinsic activity (alpha = 0.27) at the hH(3)R.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Guanidines / chemical synthesis*
  • Guanidines / chemistry
  • Guanidines / pharmacology
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Insecta
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, Histamine / genetics
  • Receptors, Histamine H4
  • Recombinant Fusion Proteins / agonists
  • Recombinant Fusion Proteins / antagonists & inhibitors
  • Recombinant Fusion Proteins / genetics
  • Structure-Activity Relationship

Substances

  • Guanidines
  • HRH4 protein, human
  • Imidazoles
  • N1-acetyl-N2-(3-(1H-imidazol-4-yl)propyl)guanidine
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Receptors, Histamine H4
  • Recombinant Fusion Proteins