Search for multifunctional agents against Alzheimer's disease among non-imidazole histamine H3 receptor ligands. In vitro and in vivo pharmacological evaluation and computational studies of piperazine derivatives
Language English Country United States Media print-electronic
Document type Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't
PubMed
31271942
DOI
10.1016/j.bioorg.2019.103084
PII: S0045-2068(19)30228-7
Knihovny.cz E-resources
- Keywords
- Acetylcholinesterase, Alzheimer’s disease, Butyrylcholinesterase, Cholinesterase inhibitors, H3 histamine receptor, Multi-target-directed ligands, Piperazine, Thiazole,
- MeSH
- Acetylcholinesterase chemistry MeSH
- Adjuvants, Anesthesia toxicity MeSH
- Alzheimer Disease drug therapy MeSH
- Amnesia chemically induced drug therapy MeSH
- Butyrylcholinesterase chemistry MeSH
- Cholinesterase Inhibitors chemistry pharmacology MeSH
- Ligands MeSH
- Disease Models, Animal * MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Mice MeSH
- Piperazines chemistry MeSH
- Receptors, Histamine H3 chemistry metabolism MeSH
- Scopolamine toxicity MeSH
- In Vitro Techniques MeSH
- Computational Biology MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Evaluation Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Adjuvants, Anesthesia MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Ligands MeSH
- Piperazines MeSH
- Receptors, Histamine H3 MeSH
- Scopolamine MeSH
In the search for new treatments for complex disorders such as Alzheimer's disease the Multi-Target-Directed Ligands represent a very promising approach. The aim of the present study was to identify multifunctional compounds among several series of non-imidazole histamine H3 receptor ligands, derivatives of 1-[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propylpiperazine, 1-[2-thiazol-4-yl-(2-aminoethyl)]-4-n-propylpiperazine and 1-phenoxyalkyl-4-(amino)alkylopiperazine using in vitro and in vivo pharmacological evaluation and computational studies. Performed in vitro assays showed moderate potency of tested compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Molecular modeling studies have revealed possible interactions between the active compounds and both AChE and BuChE as well as the human H3 histamine receptor. Computational studies showed the high drug-likeness of selected compounds with very good physicochemical profiles. The parallel artificial membrane permeation assay proved outstanding blood-brain barrier penetration in test conditions. The most promising compound, A12, chemically methyl(4-phenylbutyl){2-[2-(4-propylpiperazin-1-yl)-1,3-thiazol-5-yl]ethyl}amine, possesses good balanced multifunctional profile with potency toward studied targets - H3 antagonist activity (pA2 = 8.27), inhibitory activity against both AChE (IC50 = 13.96 μM), and BuChE (IC50 = 14.62 μM). The in vivo pharmacological studies revealed the anti-amnestic properties of compound A12 in the passive avoidance test on mice.
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