Title:Galantamine-based Hybrid Molecules with Acetylcholinesterase, Butyrylcholinesterase and γ-Secretase Inhibition Activities
Volume: 9
Issue: 5
Author(s): L. Vezenkov, J. Sevalle, D. Danalev, T. Ivanov, A. Bakalova, M. Georgieva and F. Checler
Affiliation:
Keywords:
Peptides, galantamine, alzheimer’s disease, N-(3, 4-dichlorophenyl)-D, L-Ala-OH, acetylcholinesterase, butyrylcholinesterase,
γ-secretase, inhibitors.
Abstract: We previously designed novel peptides-containing galantamine analogues. These compounds we analyzed for
their putative inhibitory effect towards acetylcholinesterase, butyrylcholinesterase and γ-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 γ-secretase inhibitory potency while they retain their ability to inhibit AChE and/or
BuChE 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.
