Overall, a series of unique synthetic methodologies are being developed in this laboratory. These organic reactions can construct complex organic structures that resemble naturally ocurring compounds. They have the potential to bring forth an array of new structures that could have therapeutic potential in Alzheimer diseases and cancer treatments. Computational means beyond the spartan program are extremely helpful in these endeavors.
Geoffrey M. Golding, Undergraduate Student Researcher
Hong Shen, Graduate Student Researcher
A rational and consistent approach for development of the therapeutic treatment of Alzheimer's Disease (AD) has been designed on the basis of the cholinergic deficiency hypothesis. This hypothesis links AD to the loss of acetylcholine, a neurotransmitter responsible for memory and cognitive functions. In the cerebral cortex and hippocampus of AD patients, the activity of choline acetyltransferase (ChAT), the enzyme that synthesizes acetylcholine, is reduced dramatically by 60-90%, thereby causing sever shortage of acetylcholine. Acetylcholine esterase (AChE), on the other hand, serves to maintain the chemical equilibrium between choline and acetylcholine by catalyzing the hydrolysis of acetylcholine to choline. With loss of the ChAT activity in AD patients, the equilibrium would clearly be shifted towards choline. To maintain concentrations of available acetylcholine in AD patients, three types of treatment have been developed based on the cholinergic deficiency hypothesis. The first one consists of administering acetylcholine equivalents in an attempt to enhance the acetylcholine level, thereby enhancing the central cholinergic activity. The second treatment involves the use of muscarinic receptor agonists selective for M1 (and M3) subtype receptor to enhance the acetylcholine uptake at the postsynaptic end. The third one involves the use of AChE inhibitors to increase the acetylcholine level at the synaptic stage by decreasing its rate of hydrolysis.
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