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
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- 作者：Makoto Ishikawa ; Rie Shinei ; Fumikazu Yokoyama ; Miki Yamauchi ; Masayo Oyama ; Kunihiro Okuma ; Takako Nagayama ; Kazuhiko Kato ; Nobukazu Kakui ; Yasuo Sato
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：May 13, 2010
- 年：2010
- 卷：53
- 期：9
- 页码：3840-3844
- 全文大小：719K
- 年卷期：v.53,no.9(May 13, 2010)
- ISSN：1520-4804
文摘
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.