Role of hydrophobic substituents on the terminal nitrogen of histamine in receptor binding and agonist activity: development of an orally active histamine type 3 receptor agonist and evaluation of its antistress activity in mice

J Med Chem. 2010 May 13;53(9):3840-4. doi: 10.1021/jm901890s.

Abstract

The terminal nitrogen atom of histamine was modified with lipophilic substituents to investigate the structure-activity relationship of histamine type 3 receptor (H3R) agonists. The introduction of an alkylated benzene rings maintained or increased the H3R binding affinity. The most potent compound, 4-(2-(4-tert-butylphenylthio)ethyl)-1H-imidazole, possessed in vivo agonistic activity, decreasing brain N(tau)-methylhistamine levels in mice after oral administration. It also exhibited antistress activity in the mouse resident-intruder test.

MeSH terms

  • Administration, Oral
  • Animals
  • Brain Chemistry
  • Histamine / analogs & derivatives*
  • Histamine / chemistry
  • Histamine Agonists / chemistry*
  • Histamine Agonists / metabolism
  • Histamine Agonists / therapeutic use
  • Hydrophobic and Hydrophilic Interactions
  • Methylhistamines / analysis
  • Mice
  • Receptors, Histamine / metabolism
  • Receptors, Histamine H3 / drug effects
  • Receptors, Histamine H3 / metabolism*
  • Stress, Psychological / drug therapy
  • Stress, Psychological / prevention & control
  • Structure-Activity Relationship

Substances

  • Histamine Agonists
  • Methylhistamines
  • Receptors, Histamine
  • Receptors, Histamine H3
  • Histamine