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Tytuł: The search for histamine H3-receptor antagonists
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This work involved the search for histamine H3 receptor antagonists in the group of 3-(1H-imidazol-4yl)propanol carbamates. The aim of this work was the synthesis of 3-(1H-imidazol-4yl)propanol carbamates and evaluation of the impact of lipophilic elements in these compounds on H3 receptor antagonist activity. Within the confines of this work 34 carbamates were designed containing N-branched alkyl-, unsaturated-, cyclohexylalkyl-, (un)substituted phenylalkyl-, or (un)substituted phenoxyalkyl- substituents. The obtained compounds were tested for their effects at histamine H3 receptor in vitro (at cloned human H3-receptor and at isolated guinea pig ileum) and (for isolated compounds) in vivo after oral administration to mice. Moreover (for isolated compounds) in vitro activity for histamine H1-, H2-receptors and muscarine M3-receptor were evaluated. In pharmacological part relationships between structure and activity were discussed in detail. Generally, obtained compounds showed from moderate to very good activity in vivo (ED50: 8,1 ÷ 0,55 [mg/kg]), only one compound was inactive at the dose to 10 mg/kg. All the compounds showed a high affinity in vitro at cloned human H3-receptors (in the nanomolar concentration range) and from moderate to good activity in the test at isolated guinea pig ileum. All tested compounds showed low affinity for H1, H2 and M3 receptors, demonstrating t ; heir selectivity for the third histamine receptor. Lipophilicity of 33 selected carbamates was eveluated experimentally by means of reversed phase thin layer chromatography (RP TLC) and by computational methods (Pallas, ChemUltra, clogP and IAlogP. The correlation of obtained experimental and theoretical results was discussed. It was attempted to find a quantitative correlation between biological activity and lipophilicity in the group of the unsatureted carbamates. It was shown that the lipophilic properties do not predominate the activity of this series of carbamates. Durability tests of selected compounds that were carried out in water, acidic and basic environment indicated their high stability to investigated conditions.
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Data ostatniej modyfikacji:
10 lut 2023
Data dodania obiektu:
21 lis 2012
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http://dl.cm-uj.krakow.pl:8080/publication/1232
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| Nazwa wydania | Data |
|---|---|
| ZB-102288 | 10 lut 2023 |
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