CI-1002, a Novel Anticholinesterase and Muscarinic Antagonist

The “cholinergic deficit hypothesis” provided the first theoretical framework for developing rational, palliative treatments for the cognitive loss associated with Alzheimer’s Disease (AD). The hypothesis arose from the synthesis of several lines of evidence showing the importance of central cholinergic function to normal cognition, and the relationship between AD dementia and the loss of cholinergic innervation to the neocortex and hippocampus (for a review see Davis et al., 1993). The “hypothesis” led to the testing of agents to restore central cholinergic function. A variety of replacement therapies were tried including inhibitors of acetylcholinesterase (AChE) to increase brain levels of acetylcholine. Initial studies using the anticholinesterase physostigmine provided suggestive evidence that such an approach might be beneficial (for a review see Kumar and Calache, 1991). However, early clinical results with tacrine (THA, Cognex®) sparked the effort to evaluate thoroughly the efficacy of cholinesterase inhibitors in the treatment of AD.