Synthesis and structure-activity relationships of N-aryl-piperidine derivatives as potent (partial) agonists for human histamine H3 receptor.
4-((1H-imidazol-4-yl)methyl)-1-aryl-piperazine and piperidine derivatives were designed and synthesized as candidate human histamine type 3 agonists. The piperazine derivatives were found to have low (or no) affinity for human histamine H3 receptor, whereas the piperidine derivatives showed moderate to high affinity, and their agonistic activity was greatly influenced by substituents on the aromatic ring. Among the piperidine-containing compounds, 17d and 17h were potent human histamine H3 receptor agonists with high selectivity over the closely related human H4 receptor. Our results indicate that appropriate conformational restriction, that is, by the piperidine spacer moiety, favors specific binding to the human histamine H3 receptor.
Ishikawa
Makoto
M
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. makoto_ishikawa@meiji.co.jp
Furuuchi
Takeshi
T
Yamauchi
Miki
M
Yokoyama
Fumikazu
F
Kakui
Nobukazu
N
Sato
Yasuo
Y
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D017442:Histamine Agonists / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D018100:Receptors, Histamine H3 / Q000378:metabolism*
D017442:Histamine Agonists; D010880:Piperidines; D018100:Receptors, Histamine H3