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
| Autor: | Anna Stasiak, Rob Leurs, Katarzyna Kieć-Kononowicz, Marek Staszewski, Tadeusz Karcz, Krzysztof Walczyński, Wiesława Agnieszka Fogel, Daniel McNaught Flores |
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| Přispěvatelé: | AIMMS, Medicinal chemistry |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Pharmacology
010405 organic chemistry Stereochemistry Organic Chemistry Pharmaceutical Science 01 natural sciences Biochemistry 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry.chemical_compound Piperazine chemistry In vivo Drug Discovery Molecular Medicine Moiety Piperidine Histamine H3 receptor Receptor Guanidine Histamine |
| Zdroj: | Staszewski, M, Stasiak, A, Karcz, T, McNaught Flores, D, Fogel, W A, Kieć-Kononowicz, K, Leurs, R & Walczyński, K 2019, ' 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 ', MedChemComm, vol. 10, no. 2, pp. 234-251 . https://doi.org/10.1039/c8md00527c MedChemComm, 10(2), 234-251. Royal Society of Chemistry |
| ISSN: | 2040-2503 |
| DOI: | 10.1039/c8md00527c |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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