Biochemistry 2002, 41, 3555-3564
3555
Kinetic and Structural Studies on the Interaction of Cholinesterases with the Anti-Alzheimer Drug Rivastigmine†,‡ P. Bar-On,§,| C. B. Millard,§,⊥ M. Harel,| H. Dvir,§,| A. Enz,@ J. L. Sussman,| and I. Silman*,§ Departments of Neurobiology and Structural Biology, Weizmann Institute of Science, RehoVot 76100, Israel, and Preclinical Research (CNS), NoVartis Pharma AG, Basel CH4002, Switzerland ReceiVed January 8, 2002
ABSTRACT: Rivastigmine, a carbamate inhibitor of acetylcholinesterase, is already in use for treatment of Alzheimer’s disease under the trade name of Exelon. Rivastigmine carbamylates Torpedo californica acetylcholinesterase very slowly (ki ) 2.0 M-1 min-1), whereas the bimolecular rate constant for inhibition of human acetylcholinesterase is >1600-fold higher (ki ) 3300 M-1 min-1). For human butyrylcholinesterase and for Drosophila melanogaster acetylcholinesterase, carbamylation is even more rapid (ki ) 9 × 104 and 5 × 105 M-1 min-1, respectively). Spontaneous reactivation of all four conjugates is very slow, with
