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

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.

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Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan.


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.

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