Alkylammonium derivatives of 6-methyluracil act as tissue-specific inhibitors of acetylcholine esterases in muscle and brain
František Vyskocil A.E.Arbusov Institute of Organic and Physical Chemistry, Russian Academy of Sciences, Kazan, Czech Republic
Abstract:
Background and purpose: Promising compounds, alkylammonium derivatives of 6-methyluracil (ADEMs), have been recently synthesized and identified as inhibitors of AChE in vitro. During exercise of dogs and rats on the treadmill, these compounds displayed surprising effects. Animals treated with ADEMs had no breathing problems and easily survived even when their limb muscles were paralyzed. We found that the rat respiratory muscle diaphragm has an up to two orders of magnitude lower sensitivity than the locomotor muscle extensor digitorum longus (EDL)s to ADEMs. This study evaluates the reasons for this inter-muscular and muscle-to- brain differences.
Experimental approach: 1. Increase in the amplitude and prolongation of the decay time of miniature end-plate currents was used as a criterion of anticholinesterase activity in muscles. 2. On hippocampus slices, non-specific anti-AChE neostigmine and tissue-specific compouns (Fig. 1) were compared in terms of their ability to induce network activity as a result of cholinesterase inhibition. 3.The C-547 sensitivities of AChE from the EDL and brain were also estimated.
Key results: The high inter-muscular difference in the sensitivity to ADEMs is partly caused by a higher activity of C-547-resistant BuChE, reflected by the higher level of mRNA and the activity of BuChE in the diaphragm. Moreover, diaphragm AChE is more than 20 times less sensitive to C-547 than that in the EDL. The EDL sensitivity to C-547 dramatically decreased after treadmill exercises, which increase the amount of PRiMA AChE (G4), but not ColQ AChE (A12). The A12 form present in muscles is probably most sensitive to C-547. The main form in the brain, PRiMA AChE (G4) is apparently less sensitive, because brain cholinesterase activity was almost three orders of magnitude more resistant to C-547 than that of the EDL.
Conclusions and implications: Our findings suggest that ADEMs can be used for the selective inhibition of AChEs and as potential therapeutic tools.
Structure of the most active compound 1,3-bis[5(diethyl-o-nitrobenzylammonium)pentyl]-6-methyluracil dibromide (C- 547)
