Abstract
Four spiroisoxazolines have been prepared, by cycloaddition of aceto-, pivalo-, benzo- and mesito-nitrile oxide with 3-methylenequinuclidine. The reactions were completely regioselective, within the limits of detection. None of the isoxazolines showed significant inhibition of acetylcholinesterase.
Highlights
Alzheimer’s disease is the most common cause of adult onset dementia.[1]. It is an incurable neuropsychiatric condition, where progressive impairment of cognitive functions, as well as affective and behavioral disturbances are observed in sufferers of the disease
Through both human[2] and animal studies,[3] a direct correlation has been established between the severity of memory impairment and a decline in choline acetyltransferase activity. This enzyme is responsible for production of the neurotransmitter acetylcholine (1) in the brain. Consistent with this observation, compounds that increase acetylcholine (1) concentration are beneficial in alleviating cognitive deficits associated with the disorder[4] and, currently, the only marketed treatments for Alzheimer’s disease are inhibitors of acetylcholinesterase,[5] the enzyme responsible for hydrolytic breakdown of acetylcholine (1) to choline (2) (Scheme 1)
The spiroisoxazolines 10a–d were prepared through cycloadditions of nitrile oxides with 3-methylenequinuclidine (12)
Summary
Alzheimer’s disease is the most common cause of adult onset dementia.[1]. It is an incurable neuropsychiatric condition, where progressive impairment of cognitive functions, as well as affective and behavioral disturbances are observed in sufferers of the disease. Consistent with this observation, compounds that increase acetylcholine (1) concentration are beneficial in alleviating cognitive deficits associated with the disorder[4] and, currently, the only marketed treatments for Alzheimer’s disease are inhibitors of acetylcholinesterase,[5] the enzyme responsible for hydrolytic breakdown of acetylcholine (1) to choline (2) (Scheme 1).
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