Development of acetylcholinesterase inhibitors in the therapy of Alzheimer's disease.
Acetylcholinesterase (AChE) inhibitors were first administered in Europe to human subjects in the 1860s, and synthetic derivatives of the natural alkaloid inhibitors were developed in the 1930s to modulate peripheral cholinergic function. However, only within the last decade have these agents been systematically studied for therapy of central cholinergic deficits. This time interval parallels the cloning of the gene and determination of the structure of the target molecule, AChE. Because AChE in mammals is encoded by a single gene and the portion of the gene encoding the catalytic domain is invariant, selectivity of action can be achieved only by altering parameters of disposition and pharmacokinetics of action of the inhibitor rather than its specificity for particular AChE isozymes in various regions of the CNS. This article describes the mechanism of action of short-acting, carbamoylating, and phosphorylating inhibitors of cholinesterase and suggests possible strategies for enhancing therapeutic efficacy.
Taylor
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Department of Pharmacology, University of California, San Diego, La Jolla 92093, USA.
D000544:Alzheimer Disease / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans
D002800:Cholinesterase Inhibitors