A Resurrection of 7-MEOTA: A Comparison with Tacrine

Ondrej      Soukup; Daniel      Jun; Jana      Zdarova-Karasova; Jiri      Patocka; Kamil      Musilek; Jan      Korabecny; Jan      Krusek; Martina      Kaniakova; Vendula      Sepsova; Jana      Mandikova; Frantisek      Trejtnar; Miroslav      Pohanka; Lucie      Drtinova; Michal      Pavlik; Gunnar      Tobin; Kamil      Kuca

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the first approved drug for the AD disease treatment, has been reported to be a multitargeted drug, however it was withdrawn from the market particularly due to its hepatotoxicity.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.

Keywords: 7-Methoxytacrine, Acetylcholinesterase inhibitor, Alzheimer´s disease drug, Cholinergic hypothesis, Pharmacological profile, Tacrine.

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