Details

Autor(en) / Beteiligte

• Cowart, Marlon
• Faghih, Ramin
• Curtis, Michael P
• Gfesser, Gregory A
• Bennani, Youssef L
• Black, Lawrence A
• Pan, Liping
• Marsh, Kennan C
• Sullivan, James P
• Esbenshade, Timothy A
• Fox, Gerard B
• Hancock, Arthur A

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2005-01, Vol.48 (1), p.38-55

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2005

Quelle

MEDLINE

Beschreibungen/Notizen

• H3 receptor antagonists based on a 2-aminoethylbenzofuran skeleton have been discovered, which are potent in vitro at human and rat H3 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 H3 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 H3 receptor antagonists for the treatment of cognitive dysfunction.