A Resurrection of 7-MEOTA: A Comparison with Tacrine

Abstract

Alzheimer´s disease (AD) is a progressive neurodegenerative dementia which currently represents one of the biggest threats for the human kind. The cure is still unknown and various hypotheses (cholinergic, amyloidal, oxidative, vascular etc.) are investigated in order to understand the pathophysiology of the disease and on this basis find an effective treatment. Tacrine, the first approved drug for the AD disease treatment, has been reported to be a multitargeted drug, however it was withdrawn from the market particularly due to its hepatotoxicity. Its derivative 7-methoxytacrine (7- MEOTA) probably due to the different metabolization does not exert this side effect. The aim of our study was to compare these two cholinesterase inhibitors from various, mainly cholinergic, points of view relevant for a potential AD drug. We found that 7-MEOTA does not fall behind its more well-known parent compound - tacrine. Furthermore, we found, that 7-MEOTA exerts better properties in most of the tests related to a possible AD treatment. Only the pharmacokinetics and a higher acetylcholinesterase and butyrylcholinesterase inhibitory potency would slightly give advantages to tacrine over 7-MEOTA, but concerning its lower toxicity, better antioxidant properties, interaction with muscarinic and nicotinic receptors and "safer" metabolization provide strong evidence for reconsider 7-MEOTA and its derivatives as candidate molecules for the treatment of AD.

Cholinergic properties of new 7-methoxytacrine-donepezil derivatives

“…However, compounds 1 and 2 inhibited AChE in comparable concentrations to those acting on the nicotinic receptor; whereas 7-MEOTA and compound 3 needed to be administered at higher concentrations to inhibit AChE. Moreover, 7-MEOTA has been evaluated previously, concerning how it influences the neuronal α4β2 nicotinic receptor (Soukup et al 2013). 7-MEOTA interacts slightly more effectively with muscular than neuronal nAChR (IC 50 = 4 µmol/l, respectively 15 µmol/l).…”

“…Except for compound 2, the drugs showed similar penetration abilities as the parent compound 7-MEOTA (Tab. 3), which has been proved to cross BBB (Soukup et al 2013). Donepezil, which was used as a model of a CNS-permeable drug, confirmed an adequate experimental setup by its high penetration rate (87%).…”

“…7-MEOTA is a pharmacologically equivalent but less toxic analogue of the parent tacrine. It also possesses a centrallyacting reversible AChE inhibition profile (Dejmek 1990) with complex cholinergic properties (Soukup et al 2013). The novel series of compounds are based on 7-MEOTA and another potent AChE inhibitor (AChEI), donepezil, which also exerts low antimuscarinic and antinicotinic properties (Ago et al 2011).…”

Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach

“…3 Computational studies performed about twenty years ago by Pang et al 14 tested the strategy of a double interaction of an inhibitor with the enzyme. 38 The authors found that methylene chain spacers joining two units of tacrine moiety allowed a double interaction of the compound with the enzyme by binding simultaneously to the CAS and PAS. 14,[38][39][40] These results lead the authors to perform the synthesis of alkylene-linked bis-tacrine compounds (Figure 1).…”

“…38 The authors found that methylene chain spacers joining two units of tacrine moiety allowed a double interaction of the compound with the enzyme by binding simultaneously to the CAS and PAS. 14,[38][39][40] These results lead the authors to perform the synthesis of alkylene-linked bis-tacrine compounds (Figure 1). 40 Among the compounds obtained, the heptylene-linked bis-tacrine (2), also called bis(7)-cognitin or bis(7)-tacrine was found to be almost fifteen hundred times more potent against AChE than tacrine.…”