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Research Areas

Developing multifunctional ligands to treat Alzheimer's disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder leading to the loss of memory and cognition. According to World Health Organization (WHO) currently there are about 24 million people worldwide with AD. With our aging population, it is estimated that the present figures on AD will more than double by 2025.

Acetylcholinesterase (AChE) inhibitors such as donepezil (Aricept®), galanthamine (Razadyne®) and rivastigmine (Exelon®) are the current mainstay of AD treatment. However, they provide only symptomatic relief. Several lines of evidence indicate that AD is a complex condition involving multiple pathways. Recent studies indicate that as AD progresses, AChE levels decline in brain whereas butyrylcholinesterase (BuChE) levels start to increase which catalyzes the degradation of the neurotransmitter acetylcholine. This mandates the need to develop agents that block both cholinesterases (AChE and BuChE).  Furthermore, in AD, AChE enzyme co-localizes with Aβ-plaques in the CNS promoting the formation of neurotoxic AChE-Aβ-peptide complex through the peripheral active site (PAS). Therefore, small molecules that bind to the peripheral site of AChE prevent the formation of neurotoxic AChE-Aβ complex. Transition metals such as Cu2+, Zn2+ and Fe3+ are implicated in neurotoxicity leading to AD and associated dementia, supporting the need to develop molecules with metal chelating ability. This calls for multiple intervention strategies to provide symptomatic relief as well as halt the disease progression where a single molecule targets multiple pathways as opposed to the traditional “one drug, one target” approach.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Development of monoamine oxidase-B (MAO-B) inhibitors

Parkinson’s disease (PD) or “shaking palsy” is a neurodegenerative disorder characterized by muscle rigidity, resting tremors and bradykinesia. More than 4 million people worldwide are affected with PD. A recent study estimates that the number of individuals with PD in fifteen of the world’s largest nations will double in the next twenty-five years.

PD is characterized by a loss or deficit in levels of the neurotransmitter dopamine (DA) in the basal ganglion. In our brain, DA is produced from neuronal cells of substantia nigra. In patients with PD there is a loss of DA producing cells in substantia nigra. The activity of DA is regulated by the enzyme MAO-B which is responsible for its metabolism (Figure 2). Paradoxically, the MAO-B catalyzed metabolism of DA can generate hydrogen peroxide (H2O2) which can cause neuronal toxicity. In addition, H2O2 can undergo redox reaction to form cytotoxic hydroxyl radicals (OH•). Consequently, selective MAO-B inhibitors should be able to block DA metabolism thereby enhancing the levels of both endogenous and exogenous DA. In addition, inhibition of DA metabolism should decrease the generation of toxic metabolites (oxidative stress) thereby providing neuroprotection. Selegiline (Eldepryl®), a selective, irreversible MAO-B inhibitor can be used as a monotherapy or in combination with Levodopa to reduce DA metabolism. A second generation selective MAO-B inhibitor rasagiline (Azilect®) was launched recently. Preclinical data has suggested that rasagiline exhibits superior neuroprotective effects compared to selegiline. Our lab is interested in the design, synthesis and biological evaluation of novel MAO inhibitors.

Figure 3: Biosynthesis and metabolism of DA