Alzheimer's Disease (AD) is threatening about 15 million people in 1994 and the number is set to rise. There are several approaches to treat this disease. One way is to inhibit AChE, an enzyme which plays an important role in AD. The most commonly used AChE inhibitor, THA, causes a serious liver abnormalities which stop patients from taking it. Fortunately, previous papers suggested that linking two THA molecules via an alkylene chain can increase it's potency and so in theory reduce liver toxicity. This result is based on the discovery of a peripheral site at the opening of AChE. In the first two chapters, the causes of AD, approaches to pharmacotherapy, and the THA-based dimers will be discussed....[ Read more ]

Alzheimer's Disease (AD) is threatening about 15 million people in 1994 and the number is set to rise. There are several approaches to treat this disease. One way is to inhibit AChE, an enzyme which plays an important role in AD. The most commonly used AChE inhibitor, THA, causes a serious liver abnormalities which stop patients from taking it. Fortunately, previous papers suggested that linking two THA molecules via an alkylene chain can increase it's potency and so in theory reduce liver toxicity. This result is based on the discovery of a peripheral site at the opening of AChE. In the first two chapters, the causes of AD, approaches to pharmacotherapy, and the THA-based dimers will be discussed.

The third chapter describes work on synthesis of novel dimeric AChE inhibitors. These inhibitors are used to provide further evidence for the existence of the peripheral site in AChE. Four series of homodimers based on THA, 4-aminopyridine, 4-aminoquinaldine and 4-chloroquinoline monomers were prepared. The new THA dimers differ from the original Pang's dimers in that the two THA molecules are linked via the cyclic nitrogens instead of the exocyclic nitrogens. Another series of THA dimers linking one THA cyclic nitrogen to the exocyclic nitrogen of another THA molecule was also prepared. Chapter three concludes with a discussion of some attempted acylation and sulfonation reactions of THA, undertaken in the hope of developing some new exocyclic N-C bond forming methods.

Chapter four describes the bio-assay results of the new dimeric inhibitor synthesized in the thesis work. AChE inhibition IC₅₀ values were determined in rat cortex homogenate, and BChE inhibition IC₅₀ values were determined in rate serum. From this data we also extract the selectivity of each dimeric inhibitor for AChE, and its potency enhancement relative to monomer. Detailed discussions on comparison within the same series, and in between different series will be given. Some conclusions can be drawn. Firstly, for those series in which comparisons can be made (A', MeB and C), dimerization enhances AChE inhibition potency by at least 100-fold. These results further confirm the existence of a functional peripheral site in AChE. Secondly, different series possess different optimum chain lengths for inhibiting the AChE but the optimum is found to lie in the range of 7-10 methylenes units. Thirdly, orientation of the cyclic nitrogen of THA towards the bottom of the active site cleft of AChE is preferred based on comparisons of the AnA and A'nA' series. Finally, the peripheral site effectively binds any 4-aminopyridine-containing ligand.