Acetylcholinesterase inhibitors



Acetylcholinesterase inhibitors


C. Bartolucci, A. Cassetta, L. Cellai, D.Lamba


Alzheimer's disease, acetylcholinesterase, carbamate, non-covalent inhibition

National Institute of Aging, National Institutes of Health, Baltimore (USA); Chemie und Chemietechnik Universität-GH Paderborn, Paderborn (Germany), Faculty of Medicine, University of Ljubljana (Slovenja); Sanochemia Pharmaceutika AG, Vienna (Austria); Chiesi Farmaceutici SpA, Parma (Italy)


Alzheimer's disease (AD) is thought to be the leading cause in senile dementia, hence the development of an effective therapeutic treatment of this disease is of primary importance and would have a great social impact. It has been shown that, associated with AD, is a loss of the cholinergic response due to reduced activity of choline acetyltransferase, the enzyme responsible for the synthesis of acetylcholine (ACh) as well as reduced levels of nicotinic ACh receptors. Hence the rational behind the current approach of cholinergic therapeutics used in the treatment of AD aims at targeting the inhibition of acetylcholinesterase (AChE) in the brain. Many years after the approval of symptomatic drugs, the improvement of old, and the development of new drugs targeting the cholinergic system is still pursued. In collaboration with pharmaceutical companies as well as academic research groups, we contributed to the screening process for new drugs showing a better pharmacokinetic as well as a pharmakodynamic profile, through the determination of the X-ray crystal structure of complexes with derivatives carefully selected among several others. In particular we determined the structures of AChE complexed with reversible (galanthamines) as well as pseudo-irreversible inhibitors (carbamat-like inhibitors).The results obtained clearly pinpointed that In order to help to direct the rational design of new inhibitors and to elucidate the molecular determinants in enzyme inhibition, the crystallographic structure determination of molecular complexes at certain milestones along the elucidation of an enzymatic process or the development of interacting inhibitory drugs based on molecular modelling appeared to be a tool of choice.

Bartolucci C, Haller LA, Jordis U, Fels G, Lamba, D. Probing Torpedo californica acetylcholinesterase catalytic gorge with two novel bis-functional galanthamine derivatives. J Med Chem (2010) 53, 745.

Bartolucci C, Siotto M, Ghidini E, Amari G, Bolzoni PT, Racchi M, Villetti G, Delcanale M, Lamba D. Structural determinants of Torpedo californica acetylcholinesterase inhibition by the novel and orally active carbamate based anti-Alzheimer drug ganstigmine (CHF-2819). J Med Chem (2006) 49, 5051.

Bartolucci C, Perola E, Pilger C, Fels G, Lamba D. Three-dimensional structure of a complex of galanthamine (Nivalin® ) with acetylcholinesterase from Torpedo californica: implications for the design of new anti-Alzheimer drugs. Proteins (2001) 42, 182.

Bartolucci C, Perola E, Cellai L, Brufani M, Lamba D. "Back door" opening implied by the crystal structure of a carbamoylated acetylcholinesterase. Biochemistry (1999) 38, 5714.




Doriano Lamba
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Last Updated (Tuesday, 21 December 2010 17:00)