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Triterpenoid cholinesterase inhibitors that might improve gait disturbances in Parkinson's disease patients

Niels V Heise, Jördis-Ann Schüler, Torje E. Orlamünde, Benjamin Brandes, Hans-Peter Deigner, Ahmed Al-Harrasi, René Csuk


: Parkinson's disease (PD) is the second most common neurodegenerative disease. Besides rigidity and tremor, patients often suffer from gait disturbance. Treatment with cholinesterase inhibitors (ChEI) has been shown to improve gait speed. Thus, the triterpene acids oleanolic acid and ursolic acid have been used as starting materials for the synthesis of compounds intended to act as inhibitors of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The parent compounds were acetylated and converted via isocyanates and amines into a series of amides, while the isocyanates were also used as starting materials for the synthesis of several urea derivatives. Screening of the compounds with the cholinesterases showed them to be good to moderate inhibitors, with ursolic acid derived isocyanate being a superior mixed-type dual inhibitor for both enzymes holding Ki values in the low mM concentration range. The data from the experiments parallel the results from molecular modeling calculations. In addition, this compound is remarkably stable in an aqueous solution and undergoes decarboxylative hydrolysis to the corresponding amine only at 50 °C after several hours.

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