title: 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.
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.
authors.affiliation: Laboratory of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. Electronic address: harusawa@gly.oups.ac.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Harusawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Sawada
authors.forename: Takuji
authors.initials: T
authors.lastname: Magata
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yoneyama
authors.forename: Lisa
authors.initials: L
authors.lastname: Araki
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Usami
authors.forename: Kouta
authors.initials: K
authors.lastname: Hatano
authors.forename: Kouichi
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamamoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamatodani
mesh_terms: D000818:Animals; D054828:Histamine H3 Antagonists / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D051381:Rats; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D054828:Histamine H3 Antagonists; D013890:Thiourea
keywords: Antagonist; Human H(3) receptor; Molecular modeling; Rat H(3) receptor; Species difference