UTILITY OF MUSCARINIC AGONISTS FOR ALZHEIMER'S DISEASE

DESCRIPTION (provided by applicant): The purpose of the present study is to assess the utility of muscarinic agonists in treating Alzheimer's disease. Levels of acetylcholine decrease in Alzheimer's disease, resulting in memory deficits. Efforts to treat Alzheimer's disease have been based on compounds that mimic acetylcholine without producing side effects such as salivation or diarrhea. Unfortunately, muscarinic agonists have shown limited clinical utility due to low efficacy, poor selectivity or high toxicity. Recent studies suggest however, that muscarinic agonists might be useful in treating not only memory impairments, but also the underlying causes of Alzheimer's disease. In particular, muscarinic agonists promote a-secretase activity, thereby limiting the production of b-amyloid, and stimulate Akt , which prevents the phosphorylation of tau proteins. Thus administration of efficacious, selective and safe muscarinic agonists could be beneficial in the early stages of Alzheimer's disease. 5-(3-Ethyl-1,2 4-oxadiazol-5-yl)-1 ,4,5,6-tetrahydropyrimidine (CDD-0 102) activates muscarinic receptors in brain and improves memory function with few side effects and low toxicity in the present study, CDD-01 02 will be examined for its ability to promote a-secretase and Akt activity. Metabolites of CDD-0102 will be determined and examined for receptor activity to assess safety. Together, the studies will assess the utility of CDD-01 02 in treating not only cognitive and memory deficits, but also the progression of Alzheimer's disease.