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Structure-activity relationships of dually-acting acetylcholinesterase inhibitors derived from tacrine on N-methyl-d-Aspartate receptors
- Source :
- European journal of medicinal chemistry. 219
- Publication Year :
- 2021
-
Abstract
- 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 þ40 mV caused by a concentration of 100 mM. 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.
- Subjects :
- Male
Quantitative Structure-Activity Relationship
Pharmacology
01 natural sciences
Receptors, N-Methyl-D-Aspartate
Membrane Potentials
03 medical and health sciences
chemistry.chemical_compound
Mice
Dogs
In vivo
Drug Discovery
medicine
Animals
Humans
Rats, Wistar
Receptor
Prepulse inhibition
030304 developmental biology
0303 health sciences
Mice, Inbred ICR
010405 organic chemistry
Organic Chemistry
Glutamate receptor
General Medicine
Psychotomimetic
Ligand (biochemistry)
Acetylcholinesterase
Recombinant Proteins
3. Good health
0104 chemical sciences
Rats
QSAR
Electrophysiology
Glutamate receptor Ion channe
Pharmacolog
y in vivo
Tacrine
chemistry
Blood-Brain Barrier
Butyrylcholinesterase
Drug Design
Cholinesterase Inhibitors
Locomotion
medicine.drug
Half-Life
Subjects
Details
- ISSN :
- 17683254
- Volume :
- 219
- Database :
- OpenAIRE
- Journal :
- European journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....7cfc3e0ae05793e4357ad120bae0352e