Pro-cognitive Effects of Dual Tacrine Derivatives Acting as Cholinesterase Inhibitors and NMDA Receptor Antagonists

Therapeutic options for Alzheimer's disease are limited. Dual compounds targeting two pathophysiological pathways concurrently may enable enhanced effect. The study focuses on tacrine derivatives acting as acetylcholinesterase (AChE) inhibitors and simultaneously as subunit-dependent N-methyl-D-aspartate (NMDA) receptor antagonists. Compounds with balanced inhibitory potencies for target proteins (K1578 and K1599) or with increased inhibitory potency for AChE (K1592 and K1594) were studied. We aimed to identify the most promising pro-cognitive compound. The pro-cognitive effects of the compounds were studied in cholinergic (scopolamine-induced) and glutamatergic (MK-801-induced) rat models of cognitive deficits in the Morris water maze. Moreover, the effect on locomotion in open field and on AChE activity in relevant brain structures were investigated. The effect of the most promising compound on NMDA receptors was explored by in vitro electrophysiology. The cholinergic antagonist scopolamine induced a deficit of memory acquisition, however was unaffected by the compounds, and a deficit of reversal learning, that was alleviated by K1578 and K1599. K1578 and K1599 significantly inhibited AChE in striatum, potentially explaining the behavioral observations. Glutamatergic antagonist dizocilpine (MK-801) induced a deficit of memory acquisition, which was alleviated by K1599. K1599 also mitigated the MK-801-induced hyperlocomotion in the open field. The electrophysiology study corroborated the K1599-associated NMDA receptor inhibitory effect. K1599 emerged as the most promising compound, demonstrating pro-cognitive efficacy in both models, consistently with intended dual effect. Our findings contributed to elucidation of structural and functional properties of tacrine derivatives associated with optimal in vivo pro-cognitive effects, which further research may benefit from. ### Competing Interest Statement The authors have declared no competing interest.