Vezenkov_2012_Curr.Alzheimer.Res_9_600

We previously designed novel peptides-containing galantamine analogues These compounds we analyzed for their putative inhibitory effect towards acetylcholinesterase butyrylcholinesterase and gamma-secretase three activities of which could be central to various neurodegenerative pathologies including Alzheimer's disease These pharmacological agents were virtually equipotent on acetylcholinesterase activity but display drastically higher inhibitory activities towards butyrylcholinesterase with several compounds displaying an about 100-fold higher activity than that harboured by galantamine Strikingly two of the galantamine amides that displayed low activity towards acetylcholinesterase exhibited the highest inhibitory potency towards butyrylcholinesterase 106 to 133 times more active than galantamine Interestingly five compounds show a rather good gamma-secretase inhibitory potency while they retain their ability to inhibit AChE and/or BCHE activity Thus we have been able to design novel compounds with significant inhibitory activity against several of the enzymes responsible for key dysfunctions taking place in several neurodegenerative diseases These mixed inhibitors could therefore be envisioned as potential pharmacological tools aimed at circumventing the degenerative processes taking place in these major pathologies.