Synthesis and evaluation of N-alkyl-S-[3-(piperidin-1-yl)propyl]isothioureas: High affinity and human/rat species-selective histamine H3 receptor antagonists |
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| Authors: | Shinya Harusawa Koichi Sawada Takuji Magata Hiroki Yoneyama Lisa Araki Yoshihide Usami Kouta Hatano Kouichi Yamamoto Daisuke Yamamoto Atsushi Yamatodani |
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| Institution: | 1. Laboratory of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan;2. Department of Bioinformatics, Graduate School of Allied Health Sciences, Faculty of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan;3. Biomedical Computation Center, Osaka Medical College, 2-7 Daigakucho, Takatsuki, Osaka 569-8686, Japan |
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| Abstract: | S-Alkyl-N-alkylisothiourea compounds containing various cyclic amines were synthesized in the search for novel nonimidazole histamine H3 receptor (H3R) antagonists. Among them, four N-alkyl S-3-(piperidin-1-yl)propyl]isothioureas 18, 19, 22, and 23 were found to exhibit potent and selective H3R antagonistic activities against in vitro human H3R, but were inactive against in vitro human H4R. Furthermore, three alkyl homologs 18–20 showed inactivity for histamine release in in vivo rat brain microdialysis, suggesting differences in antagonist affinities between species. In addition, in silico docking studies of N-4-(4-chlorophenyl)butyl]-S-3-piperidin-1-yl)propyl]isothiourea 19 and a shorter homolog 17 with human/rat H3Rs revealed that structural differences between the antagonist-docking cavities of rat and human H3Rs were likely caused by the Ala122/Val122 mutation. |
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| Keywords: | Antagonist Species difference Molecular modeling |
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