Structural determinants of Torpedo californica acetylcholinesterase inhibition by the novel and orally active carbamate based anti-alzheimer drug ganstigmine (CHF-2819).

Abstract	Ganstigmine is an orally active, geneserine derived, carbamate-based acetylcholinesterase inhibitor developed for the treatment of Alzheimer's disease. The crystal structure of the ganstigmine conjugate with Torpedo californica acetylcholinesterase (TcAChE) has been determined at 2.40 A resolution, and a detailed structure-based analysis of the in vitro and ex vivo anti-AChE activity by ganstigmine and by new geneserine derivatives is presented. The carbamoyl moiety is covalently bound to the active-site serine, whereas the leaving group geneseroline is not retained in the catalytic pocket. The nitrogen atom of the carbamoyl moiety of ganstigmine is engaged in a key hydrogen-bonding interaction with the active site histidine (His440). This result offers an explanation for the inactivation of the catalytic triad and may account for the long duration of action of ganstigmine in vivo. The 3D structure also provides a structural framework for the design of compounds with improved binding affinity and pharmacological properties.
Authors	Cecilia Bartolucci, Mariacristina Siotto, Eleonora Ghidini, Gabriele Amari, Pier Tonino Bolzoni, Marco Racchi, Gino Villetti, Maurizio Delcanale, Doriano Lamba
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 49 Issue 17 Pg. 5051-8 (Aug 24 2006) ISSN: 0022-2623 [Print] United States
PMID	16913695 (Publication Type: Comparative Study, Journal Article)
Chemical References	Alkaloids Carbamates Cholinesterase Inhibitors geneserine Acetylcholinesterase ganstigmine
Topics	Acetylcholinesterase (chemistry, drug effects) Administration, Oral Alkaloids (administration & dosage, chemistry, pharmacology) Alzheimer Disease (drug therapy) Animals Binding Sites (drug effects) Brain (enzymology) Carbamates (administration & dosage, chemistry, pharmacology) Cholinesterase Inhibitors (administration & dosage, chemistry, pharmacology) Crystallization Crystallography, X-Ray Drug Evaluation, Preclinical Enzyme Activation (drug effects) Male Mice Models, Molecular Molecular Conformation Stereoisomerism Structure-Activity Relationship Torpedo

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