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Issue 2, 2019
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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 H3 receptor antagonists

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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 H3 receptor with pA2 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 H3 receptor. Additionally, the most active compounds 1a, 1c, and 1d were evaluated for their affinity to the rat histamine H3 receptor and the human histamine H3 and H4 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.

Graphical abstract: 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 H3 receptor antagonists

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Publication details

The article was received on 18 Oct 2018, accepted on 29 Nov 2018 and first published on 11 Jan 2019


Article type: Research Article
DOI: 10.1039/C8MD00527C
Med. Chem. Commun., 2019,10, 234-251

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    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 H3 receptor antagonists

    M. Staszewski, A. Stasiak, T. Karcz, D. McNaught Flores, W. A. Fogel, K. Kieć-Kononowicz, R. Leurs and K. Walczyński, Med. Chem. Commun., 2019, 10, 234
    DOI: 10.1039/C8MD00527C

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