Structure-activity relationships of dually-acting acetylcholinesterase inhibitors derived from tacrine on N-methyl-D-Aspartate receptors

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.