Investigation of the Histamine H3 Receptor Binding Site. Design and Synthesis of Hybrid Agonists with a Lipophilic Side Chain

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• 作者：Makoto Ishikawa ; Takashi Watanabe ; Toshiaki Kudo ; Fumikazu Yokoyama ; Miki Yamauchi ; Kazuhiko Kato ; Nobukazu Kakui ; Yasuo Sato
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：September 9, 2010
• 年：2010
• 卷：53
• 期：17
• 页码：6445-6456
• 全文大小：1035K
• 年卷期：v.53,no.17(September 9, 2010)
• ISSN：1520-4804

文摘

As a part of our search for novel histamine H3 receptor agonists, we designed and synthesized hybrid compounds in which the lipophilic (4′-alkylphenylthio)ethyl moiety of a novel H3 receptor agonist, 4-(2-(4′-tert-butylphenylthio)ethyl)-1H-imidazole (1), was incorporated into N^α-methylhistamine, immepip, and immethridine derivatives. These hybrid compounds were expected to interact concurrently with the histamine-binding site and a putative hydrophobic region in the H3 receptor. Among them, piperidine- and pyridine-type derivatives displayed partial agonist activity, and (S)-4-(1-(1H-imidazol-4-yl)-2-(4-(trifluoromethyl)phenylthio)ethyl)piperidine (36) was identified as a potent H3 agonist. We performed computational docking studies to examine the binding mode of the agonists. The results indicated that immepip interacts with the key residues, Asp114 and Glu206, in a different manner from histamine. The binding mode of 36 to these residues is similar to that of immepip, and the lipophilic tail of 36 has an additional interaction with a hydrophobic region in transmembrane helix 6 of the receptor. These results indicated that 36 served as a useful tool for studies on receptor−agonist interactions and drug design.