The effects of novel 7-MEOTA-donepezil like hybrids and N-alkylated tacrine analogues in the treatment of quinuclidinyl benzilate-induced behavioural deficits in rats performing the multiple T-maze test

Abstract

Aims. The number of approved drugs for the clinical treatment of Alzheimer disease remains limited. For this reason, there is extensive search for novel therapies. Of these, cholinesterase inhibitors have some proven benefit in slowing the disease progression and still remain the first-line therapeutic approach. In this study, the pro-cognitive effect of four novel tacrine-related inhibitors was evaluated and compared with the standards, tacrine and donepezil. Methods. Wistar rats trained to perform the multiple T-maze were treated intra-peritoneally with the anticholinergic agent 3-quinuclidinyl benzilate (QNB, 2.0 mg/kg), followed 30 min later by another injection containing a therapeutic dose of standard or novel cholinesterase inhibitor. The rats were repeatedly subjected to the multiple T-maze task at several time points following QNB administration (1, 24, 48 and 72 h). The passage time and number of errors were recorded. The inhibitory potential of selected therapeutic doses was assessed in a separate in vivo experiment using a spectrophotometric method. Results. QNB significantly impaired the performance of the rats within 48 h. The four novel cholinesterase inhibitors attenuated the effect of QNB at 1 h, 24 h and 48 h test intervals. The novel compounds resulted in brain cholinesterase inhibition ranging from 5.4 to 11.3 %, and their effect on the QNB-induced deficit recorded in the T-maze performance was comparable to that of the standards or higher at some time points. Conclusion: The best result was achieved with derivative 4, followed by derivatives 2 and 3, suggesting that these compounds could be candidates for the treatment of Alzheimer disease.

Novel Tacrine-Scutellarin Hybrids as Multipotent Anti-Alzheimer’s Agents: Design, Synthesis and Biological Evaluation

“…Such an orientation of THA scaffold is highly consistent with other recently described THA dual binders like tacrine-tianeptine or 7-methoxytacrine-adamantylamine heterodimers [ 65 , 66 , 67 ]. On contrary, it has to be stated that opposite orientation, i.e., THA lodging within PAS region, can be also found in the literature like in 7-methoxytacrine- p -anisidine, tacrine-Trolox or 7-methoxytacrine-donepezil like compounds [ 68 , 69 , 70 ]. In case of K1383 , the 6-Cl-THA moiety is facing Trp86 (4.1 Å) in a π-π/cation-π parallel manner.…”

Management of oxidative stress and other pathologies in Alzheimer’s disease

“…A similar stereochemical orientation has also been reported for tacrine-tianeptine or 7-methoxytacrine-adamantylamine hybrids (Ceschi et al 2016;Spilovska et al 2013;Korabecny et al 2015). An opposite arrangement, in which tacrine interacts with PAS has been reported for 7-methoxytacrine-p-anisidine (Korabecny et al 2015), 7-methoxytacrine-donepezil (Misik et al 2015) and tacrine-trolox heterodimers (Nepovimova et al 2015). p-Anisidine is known to suppress intracellular accumulation of the precursor to the neurotoxic Aβ, APP.…”

The New Acetylcholinesterase Inhibitors PC‐37 and PC‐48 (7‐Methoxytacrine‐Donepezil‐Like Compounds): Characterization of Their Metabolites in Human Liver Microsomes, Pharmacokinetics and In Vivo Formation of the Major Metabolites in Rats

“…These compounds as reversible AChE inhibitors have also other anticholinergic effects; in vitro and ex vivo experiments showed that they can inhibit also nicotinic (nAChR) and muscarinic cholinergic receptors (mAChR) of both peripheral and central types . Thus, these compounds may also diminish the effect of cholinergic receptor overstimulation during organophosphate poisoning . The potential pharmacodynamic effects were described but in vivo pharmacokinetic parameters of the compounds are still missing in the literature.…”