Date of Award

1-1-2011

Document Type

Campus Access Dissertation

Department

College of Pharmacy

Sub-Department

Pharmaceutical Science

First Advisor

James M Chapman

Abstract

Alzheimer's disease (AD) is the most common type of dementia in the elderly. Currently, there is no preventive or curative treatment available for this disease and it has become the sixth leading cause of death for people of all ages and the fifth leading cause of death in people age 65 and older. The multifactorial nature of AD makes "multi-target- directed ligands" (MTDLs) a potentially effective avenue to develop disease modifying drug candidates.

A ranitidine analog, JWS-USC-75-IX (JWS,[(3-[[[2-[[(5-dimethylamino methyl)-2-furanyl]methyl]thio]ethyl]amino]-4-nitropyridazine) has demonstrated both AChE inhibition and M2 receptor antagonism at submicromolar concentrations in in vitro assays, which provides a prototypical compound for a new class of MTDLs for the potential therapy of AD. In the present study, JWS was resynthesized utilizing optimized methodology and tested in rodent and non-human primate models, which revealed that JWS not only improved some cognition-related task functions in animal models but also might be useful in neuropsychiatric conditions. Molecular modeling studies were further utilized to demonstrate that JWS bonded to AChE at both the CAS and PAS binding sites with its noncovalent interactions being similar to the binding mode of donepezil. The hydrophobic and &pi-&pi interactions play an important role in the potent inhibitory activities. Based on these results, a series of JWS derivatives and 1,8-naphthalimide analogs were synthesized as potential MTDLs and tested for their AChE inhibitory, muscarinic receptor binding, A&beta aggregation inhibitory and iNOS inhibitory activities. The structure-activity relationships of these JWS derivatives as AChE inhibitors and of the 1,8-naphthalimide analogs as A&beta aggregation inhibitors were explored and summarized. Among the compounds tested in this study, compound 35, a JWS analog possessing a 3-NO2-1, 8-naphthalimide moiety, revealed potent AChE inhibition (IC50=150nM, similar to donepezil IC50=56nM) and Aâ aggregation inhibition(a 71.8% of plateau reduction). Compound 55, a 1,8-(napthalimido)-phenol analog, demonstrated potent Aâ aggregation inhibiton (85.2% of plateau reduction and a 4.9 fold extension of lag time) and potential iNOS reduction. Compound 55 was also shown to inhibit the growth of soluble aggregates by both association and elongation inhibition. In addition, compound 56 which bears a 1,8-naphthalimide group connected to a 2-dimethylaminofuran group by a two-carbon linker demonstrated potent Aâ aggregation inhibitions (65.6% of plateau reduction and a 2.25 fold lag time extension) and potential AChE inhibitory activity.

Overall, although the present structural modifications of JWS make the resulting compounds lose their modestly selective M2 inhibition, compounds 35, 55 and 56 combine more than one biological activity which might be beneficial in the treatment of AD. The compounds studied herein provide the impetus to develop a new class of MTDLs for the therapy of AD. These inherent structural elements can be optimized to further enhance the chemical stability and the various inhibitory capabilities of these compounds, and thus advance the rational design of MTDLs and aid in the understanding of the heterogeneous pathologies of AD.

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