A selective human H(4)-receptor agonist: (-)-2-cyano-1-methyl-3-[(2R,5R)-5- [1H-imidazol-4(5)-yl]tetrahydrofuran-2-y] methylguanidine

J Med Chem. 2003 Jul 3;46(14):3162-5. doi: 10.1021/jm0300025.

Abstract

A series of 16 compounds related to chiral 4(5)-(5-aminomethyltetrahydrofuran-2-yl)imidazoles (1) have been designed, synthesized, and examined in vitro by radioligand displacement studies and functional assays for both the human H(3)- and H(4)-receptors expressed in SK-N-MC cells. Among them, the (2S,5S)-isomer 1d of amino compounds showed approximately 300-fold higher selectivity at the H(3)-receptor than the H(4)-receptor. On the other hand, (2R,5S)- and (2R,5R)-cyanoguanidines 3b and 3c, in which the amino group of the compounds 1b and 1c was substituted by the cyanoguanidino moiety, bound to the H(4)-receptor with a pEC(50) value of 6.65 and 7.11, respectively, and had >40-fold selectivities over the H(3)-receptor. As such, 3b and 3c are the first selective H(4) receptor agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • Cell Line
  • Histamine Agonists / chemical synthesis*
  • Histamine Agonists / chemistry
  • Histamine Agonists / pharmacology
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Methylguanidine / analogs & derivatives
  • Methylguanidine / chemical synthesis*
  • Methylguanidine / chemistry
  • Methylguanidine / pharmacology
  • Receptors, G-Protein-Coupled*
  • Receptors, Histamine / metabolism*
  • Receptors, Histamine H3 / metabolism
  • Receptors, Histamine H4
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 2-cyano-1-methyl-3-(5-(1H-imidazol-4(5)-yl)tetrahydrofuran-2-yl)methylguanidine
  • HRH4 protein, human
  • Histamine Agonists
  • Imidazoles
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Receptors, Histamine H3
  • Receptors, Histamine H4
  • Methylguanidine