Design, synthesis, and: In vitro and in vivo characterization of 1-{4-[4-(substituted)piperazin-1-yl]butyl}guanidines and their piperidine analogues as histamine H 3 receptor antagonists

Marek Staszewski, Anna Stasiak, Tadeusz Karcz, Daniel McNaught Flores, Wiesława Agnieszka Fogel, Katarzyna Kieć-Kononowicz, Rob Leurs, Krzysztof Walczyński

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Abstract

Previously, we have shown that 1-substituted-[4-(7-phenoxyheptylpiperazin-1-yl)butyl]guanidine with electron withdrawing substituents at position 4 in the benzyl moiety exhibits high in vitro affinities toward the guinea pig jejunal histamine H 3 receptor with pA 2 ranging from 8.49 to 8.43. Here, we present data on the impact of replacement of the piperazine scaffold by the piperidine ring (compounds 2a and 2b), moving benzyl- and 4-trifluoromethylbenzyl substituents from position 1 to 3 of the guanidine moiety (compounds 2c and 2d), which decreases the guanidine basicity (compound 2e), and the influence of individual synthons (compounds 2f-h), present in the lead compounds 1b and 1c, on the antagonistic activity against the histamine H 3 receptor. Additionally, the most active compounds 1a, 1c, and 1d were evaluated for their affinity to the rat histamine H 3 receptor and the human histamine H 3 and H 4 receptors. It was also shown that compounds 1a, 1c and 1d, given parenterally for five days, reduced the food intake of rats and did not influence the brain histamine or noradrenaline concentrations; however, significantly reduced serotonin and dopamine concentrations were found in rats administered with compounds 1a and 1c, respectively.

Original languageEnglish
Pages (from-to)234-251
Number of pages18
JournalMedChemComm
Volume10
Issue number2
DOIs
Publication statusPublished - 1 Feb 2019

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