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Identification of histamine H3 receptor antagonists
Author(s) -
Del Tredici Andria Lee,
Eskildsen Jorgen,
Andersen Carsten B,
Ma Jiang,
Ohrmund Steven,
Petersen Lauren,
Littler PeyLih,
Nugyen Derek,
Fairbairn Luke,
Lameh Jelveh,
Currier Erika A,
Schiffer Hans H,
Burstein Ethan,
Olsson Roger,
Piu Fabrice
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a790-d
Subject(s) - histamine h3 receptor , histamine , antagonist , chemistry , pharmacology , thioperamide , agonist , receptor , g protein coupled receptor , biology , biochemistry
Histamine H 3 receptors (H 3 R) regulate the release of histamine and other neurotransmitters in the brain. H 3 R have been shown to modulate many functions, including feeding, sleep, and cognition, making them attractive drug targets. We have developed a functional cell‐based assay, R‐SAT® (Receptor Selection and Amplification Technology) which is predictive of agonist and antagonist activity at H 3 R. Using R‐SAT, we have screened over 250,000 small molecule compounds for antagonist activity at H 3 R. Over 10 non‐imidazole chemotypes were identified with potent human H 3 activity. Most of these chemistries also displayed similar potencies at the rat H 3 receptor with weak or no detectable activity at human H 1 , H 2 , or H 4 receptors. These compounds can also antagonize histamine‐induced intracellular release of calcium at H 3 R, and some compounds can inhibit basal cAMP activity at H 3 R. Differences in the affinities of these compounds for various H 3 R splice variants were also observed. Moreover, one of these compounds, H3‐381, significantly reduced food intake in fasted rats. These novel and selective compounds may be useful leads for the development of H 3 R antagonist therapeutics.