With the incidence of Alzheimer’s disease (AD) growing worldwide and in Canada along with the growing economic and social burdens, the need for more effective therapies becomes of great importance. Since the discovery of AD, a number of proposed theories have arisen to explain the pathophysiology including the i) cholinergic theory, ii) oxidative stress pathways, and iii) metal ion imbalance. The major class of drug therapies to treat AD are cholinesterase inhibitors; however, the “one drug, one target” approach has not proven fruitful and generally becomes ineffective in later stages of disease progression. In this project, we synthesized a library of 1,2,3,4-tetrahydroacridine derivatives (10a-d, 11a-e, 12a-e, and 13a-f) as potential agents to target the cholinergic and oxidative stress pathways of AD. Chapter I provides background information on the role of AChE and BuChE enzymes in AD. Furthermore, this chapter describes the neurotoxicity of reactive oxygen species (ROS) and metals in AD. Chapter II provides a summary of project hypothesis and rationale. Chapter III describes the synthetic details regarding the synthesis of target small molecules. It further describes the principles involved in carrying out biological evaluation such as AChE and BuChE inhibition, antioxidant properties via DPPH stable radical scavenging, iron chelation capacity using ferrozine and in vitro cell viability data in neuroblastoma cells. Chapter IV describes the SAR details on ChE inhibition, antioxidant activities, iron chelation and cell viability profiles and molecular modeling details. A brief conclusion and future directions are included in Chapter V and the final section, Chapter VI provides experimental details for synthetic chemistry including analytical data of synthesized compounds and protocols for biological evaluations. This study identified novel tetrahydroacridine derivatives with nanomolar inhibition of both human AChE and human BuChE enzymes that were more potent relative to the reference agent tacrine. Compound 10d[N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine] was identified as a potent inhibitor of BuChE (IC50 = 24.0 nM) and compound 13c [6-chloro-N-(pyridine- 2-ylmethyl)-1,2,3,4-tetrahydroacridin-9-amine] was identified as a potent inhibitor of AChE (IC50 = 95.0 nM) with good inhibition of BuChE (IC50 = 1.61 μM) whereas compound 11e [6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine] was identified with an optimum combination of dual AChE and BuChE inhibition (AChE IC50 = 0.9 μM; BuChE IC50= 1.4 μM). In conclusion, our studies provide new insight into the design and development of novel tetrahydroacridine derivatives to target multiple pathological routes of AD.

Abstract Background: Home care is an important care setting for those with Alzheimer’s disease (AD). It provides support that allows individuals with AD to remain at home and may delay the transition to long-term care homes. Many clients with AD receive medications that are used for managing the symptoms of AD: cholinesterase inhibitors (ChEIs) and memantine. Ontario’s provincial drug benefit plan (ODB) provides subsidies for some of these medications based on specific clinical criteria. These AD medications are costly and can have significant side effects, so it is important to understand how they are being used in practice. Objectives: The objectives of this study were to report the proportion taking AD medications and which types were taken, show the change in receipt of AD medications over time, and show the covariates that were independently associated with receiving AD medications. Methods: Analysis of secondary data was performed on the provincial home care dataset. All home care clients receiving long-term home care services were assessed using the RAI-Home Care (RAI-HC), which is a comprehensive and standardized assessment. One assessment from each individual over the age of 65 who was assessed between January 2004 and September 2008 was used, for a final sample size of 321,013. Results: Overall, 65% of clients with a diagnosis of AD were receiving an AD medication. Logistic regression analysis among those diagnosed with AD showed that increased physical impairment and clinical complexity were associated with decreased odds of receiving AD medication. Contraindicating diagnoses such as congestive heart failure, lack of medical oversight and needing to make economic tradeoffs were also associated with decreased odds of receiving AD medication. Conclusions: The multivariate model showed trends of rational prescribing, such as clients with contraindicating diagnoses or very high clinical complexity having decreased odds of receiving AD medications. At the same time, evidence of structural barriers to receiving the medications was shown. There is debate about the cost-effectiveness of these medications. The provincial government could consider expanding ODB guidelines to include all AD medications for those with all levels of cognitive impairment, but further analyses involving longitudinal outcomes available in this dataset should be performed to ensure it would be in the public interest.

Abstract Background: Home care is an important care setting for those with Alzheimer’s disease (AD). It provides support that allows individuals with AD to remain at home and may delay the transition to long-term care homes. Many clients with AD receive medications that are used for managing the symptoms of AD: cholinesterase inhibitors (ChEIs) and memantine. Ontario’s provincial drug benefit plan (ODB) provides subsidies for some of these medications based on specific clinical criteria. These AD medications are costly and can have significant side effects, so it is important to understand how they are being used in practice. Objectives: The objectives of this study were to report the proportion taking AD medications and which types were taken, show the change in receipt of AD medications over time, and show the covariates that were independently associated with receiving AD medications. Methods: Analysis of secondary data was performed on the provincial home care dataset. All home care clients receiving long-term home care services were assessed using the RAI-Home Care (RAI-HC), which is a comprehensive and standardized assessment. One assessment from each individual over the age of 65 who was assessed between January 2004 and September 2008 was used, for a final sample size of 321,013. Results: Overall, 65% of clients with a diagnosis of AD were receiving an AD medication. Logistic regression analysis among those diagnosed with AD showed that increased physical impairment and clinical complexity were associated with decreased odds of receiving AD medication. Contraindicating diagnoses such as congestive heart failure, lack of medical oversight and needing to make economic tradeoffs were also associated with decreased odds of receiving AD medication. Conclusions: The multivariate model showed trends of rational prescribing, such as clients with contraindicating diagnoses or very high clinical complexity having decreased odds of receiving AD medications. At the same time, evidence of structural barriers to receiving the medications was shown. There is debate about the cost-effectiveness of these medications. The provincial government could consider expanding ODB guidelines to include all AD medications for those with all levels of cognitive impairment, but further analyses involving longitudinal outcomes available in this dataset should be performed to ensure it would be in the public interest.