4-(2-[2-(2(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile and related 2-aminoethylbenzofuran H3 receptor antagonists potently enhance cognition and attention

J Med Chem. 2005 Jan 13;48(1):38-55. doi: 10.1021/jm040118g.


H(3) receptor antagonists based on a 2-aminoethylbenzofuran skeleton have been discovered, which are potent in vitro at human and rat H(3) receptors, with K(i) values of 0.1-5.8 nM. Analogues were discovered with potent (0.01-1 mg/kg) cognition and attention enhancing properties in animal models. One compound in particular, 4-(2-[2-(2(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile (ABT-239), combined potent and selective H(3) receptor antagonism and excellent pharmacokinetic and metabolic properties across species, with full efficacy in two behavioral models: a five-trial inhibitory avoidance acquisition model in rat pups at 0.1 mg/kg and a social recognition memory model in adult rats at 0.01 mg/kg. Furthermore, this compound did not stimulate locomotor activity and showed high selectivity for the induction of behavioral efficacy versus central nervous system based side effects. The potency and selectivity of this compound and of analogues from this class support the potential of H(3) receptor antagonists for the treatment of cognitive dysfunction.

MeSH terms

  • Administration, Oral
  • Animals
  • Attention / drug effects*
  • Avoidance Learning / drug effects
  • Behavior, Animal / drug effects
  • Benzofurans / chemistry
  • Benzofurans / pharmacology*
  • Biological Availability
  • Blood Proteins / metabolism
  • Central Nervous System / drug effects
  • Central Nervous System Agents / chemistry
  • Central Nervous System Agents / pharmacology
  • Cognition / drug effects*
  • Cytochrome P-450 Enzyme System / drug effects
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods
  • Haplorhini
  • Histamine Antagonists / chemistry
  • Histamine Antagonists / pharmacokinetics
  • Histamine Antagonists / pharmacology*
  • Humans
  • Memory / drug effects
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Rats
  • Receptors, Histamine H3 / drug effects*
  • Social Behavior
  • Structure-Activity Relationship


  • Benzofurans
  • Blood Proteins
  • Central Nervous System Agents
  • Histamine Antagonists
  • Pyrrolidines
  • Receptors, Histamine H3
  • benzonitrile, 4-(2-(2-((2r)-2-methyl-1-pyrrolidinyl)ethyl)-5-benzofuranyl)-
  • Cytochrome P-450 Enzyme System