Multitarget-Directed Ligands Combining Cholinesterase and Monoamine Oxidase Inhibition with Histamine H3 R Antagonism for Neurodegenerative Diseases
Language English Country Germany Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- antioxidants, drug design, inhibitors, multitarget drugs, neurological agents,
- MeSH
- Histamine H3 Antagonists chemical synthesis chemistry pharmacokinetics therapeutic use MeSH
- Antioxidants chemical synthesis chemistry pharmacokinetics therapeutic use MeSH
- Cholinesterase Inhibitors chemical synthesis chemistry pharmacokinetics therapeutic use MeSH
- Blood-Brain Barrier metabolism MeSH
- Indoles chemical synthesis chemistry pharmacokinetics therapeutic use MeSH
- Monoamine Oxidase Inhibitors chemical synthesis chemistry pharmacokinetics therapeutic use MeSH
- Cognitive Dysfunction drug therapy metabolism MeSH
- Humans MeSH
- Ligands MeSH
- Mice MeSH
- Neurodegenerative Diseases drug therapy metabolism MeSH
- Neuroprotective Agents chemical synthesis chemistry pharmacokinetics therapeutic use MeSH
- Piperidines chemical synthesis chemistry pharmacokinetics therapeutic use MeSH
- Drug Design MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Histamine H3 Antagonists MeSH
- Antioxidants MeSH
- Cholinesterase Inhibitors MeSH
- Indoles MeSH
- Monoamine Oxidase Inhibitors MeSH
- Ligands MeSH
- N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine MeSH Browser
- Neuroprotective Agents MeSH
- Piperidines MeSH
The therapy of complex neurodegenerative diseases requires the development of multitarget-directed drugs (MTDs). Novel indole derivatives with inhibitory activity towards acetyl/butyrylcholinesterases and monoamine oxidases A/B as well as the histamine H3 receptor (H3R) were obtained by optimization of the neuroprotectant ASS234 by incorporating generally accepted H3R pharmacophore motifs. These small-molecule hits demonstrated balanced activities at the targets, mostly in the nanomolar concentration range. Additional in vitro studies showed antioxidative neuroprotective effects as well as the ability to penetrate the blood-brain barrier. With this promising in vitro profile, contilisant (at 1 mg kg-1 i.p.) also significantly improved lipopolysaccharide-induced cognitive deficits.
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