S-Alkyl-N-alkylisothiourea compounds containing various cyclic amines were synthesized in the search for novel nonimidazole histamine H 3 receptor (H 3 R) 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 H 3 R antagonistic activities against in vitro human H 3 R, but were inactive against in vitro human H 4 R. 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 H 3 Rs revealed that structural differences between the antagonist-docking cavities of rat and human H 3 Rs were likely caused by the Ala122/Val122 mutation. © 2013 Elsevier Ltd. All rights reserved.
Harusawa, S., Sawada, K., Magata, T., Yoneyama, H., Araki, L., Usami, Y., … Yamatodani, A. (2013). Synthesis and evaluation of N-alkyl-S-[3-(piperidin-1-yl)propyl] isothioureas: High affinity and human/rat species-selective histamine H 3 receptor antagonists. Bioorganic and Medicinal Chemistry Letters, 23(23), 6415–6420. https://doi.org/10.1016/j.bmcl.2013.09.052