Structure-activity relationships of dually-acting acetylcholinesterase inhibitors derived from tacrine on N-methyl-d-Aspartate receptors
Language English Country France Media print-electronic
Document type Journal Article
PubMed
33892271
DOI
10.1016/j.ejmech.2021.113434
PII: S0223-5234(21)00283-X
Knihovny.cz E-resources
- Keywords
- Acetylcholinesterase, Electrophysiology, Glutamate receptor, Ion channel, Pharmacology, QSAR, Tacrine, in vivo,
- MeSH
- Acetylcholinesterase chemistry genetics metabolism MeSH
- Butyrylcholinesterase chemistry metabolism MeSH
- Cholinesterase Inhibitors chemistry metabolism pharmacology MeSH
- Blood-Brain Barrier drug effects metabolism MeSH
- Rats MeSH
- Quantitative Structure-Activity Relationship MeSH
- Humans MeSH
- Locomotion drug effects MeSH
- Membrane Potentials drug effects MeSH
- Mice, Inbred ICR MeSH
- Mice MeSH
- Half-Life MeSH
- Rats, Wistar MeSH
- Dogs MeSH
- Drug Design MeSH
- Receptors, N-Methyl-D-Aspartate antagonists & inhibitors genetics metabolism MeSH
- Recombinant Proteins biosynthesis chemistry MeSH
- Tacrine chemistry metabolism pharmacology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Mice MeSH
- Dogs MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Butyrylcholinesterase MeSH
- Cholinesterase Inhibitors MeSH
- Receptors, N-Methyl-D-Aspartate MeSH
- Recombinant Proteins MeSH
- Tacrine MeSH
Tacrine is a classic drug whose efficacy against neurodegenerative diseases is still shrouded in mystery. It seems that besides its inhibitory effect on cholinesterases, the clinical benefit is co-determined by NMDAR-antagonizing activity. Our previous data showed that the direct inhibitory effect of tacrine, as well as its 7-methoxy derivative (7-MEOTA), is ensured via a "foot-in-the-door" open-channel blockage, and that interestingly both tacrine and 7-MEOTA are slightly more potent at the GluN1/GluN2A receptors when compared with the GluN1/GluN2B receptors. Here, we report that in a series of 30 novel tacrine derivatives, designed for assessment of structure-activity relationship, blocking efficacy differs among different compounds and receptors using electrophysiology with HEK293 cells expressing the defined types of NMDARs. Selected compounds (4 and 5) potently inhibited both GluN1/GluN2A and GluN1/GluN2B receptors; other compounds (7 and 23) more effectively inhibited the GluN1/GluN2B receptors; or the GluN1/GluN2A receptors (21 and 28). QSAR study revealed statistically significant model for the data obtained for inhibition of GluN1/Glu2B at -60 mV expressed as IC50 values, and for relative inhibition of GluN1/Glu2A at +40 mV caused by a concentration of 100 μM. The models can be utilized for a ligand-based virtual screening to detect potential candidates for inhibition of GluN1/Glu2A and/or GluN1/Glu2B subtypes. Using in vivo experiments in rats we observed that unlike MK-801, the tested novel compounds did not induce hyperlocomotion in open field, and also did not impair prepulse inhibition of startle response, suggesting minimal induction of psychotomimetic side effects. We conclude that tacrine derivatives are promising compounds since they are centrally available subtype-specific inhibitors of the NMDARs without detrimental behavioral side-effects.
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