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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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posted on 2010-05-13, 00:00 authored by Makoto Ishikawa, Rie Shinei, Fumikazu Yokoyama, Miki Yamauchi, Masayo Oyama, Kunihiro Okuma, Takako Nagayama, Kazuhiko Kato, Nobukazu Kakui, Yasuo Sato
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 Nτ-methylhistamine levels in mice after oral administration. It also exhibited antistress activity in the mouse resident−intruder test.