Tryptamine: A privileged scaffold for the management of Alzheimer's disease

Alzheimer's disease (AD) is a chronic and irreversible neurodegenerative disease associated with aging. It is characterized by the progressive loss of memory and other cognitive functions. Although the exact etiology of AD is not well explored, several factors, such as the deposition of amyloid-β (Aβ) plaques, hyperphosphorylation of tau protein, presence of low levels of acetylcholine, and generation of oxidative stress, are key mediators in the progression of AD. Currently, the clinical treatment options for AD are limited and are based on cholinesterase (ChE) inhibitors (e.g., donepezil, rivastigmine, and galantamine), N-methyl-d-aspartic acid receptor antagonists (e.g., memantine), and the recently approved Aβ modulator (e.g., aducanumab). Tryptamine (2-(1H-indol-3-yl)ethan-1-amine) is a small molecule that contains an indole nucleus and an ethylamine side chain. It is also the active metabolite of tryptophan. It possesses a wide range of biological activities related to neurodegenerative disorders, such as ChE inhibition, Aβ aggregation inhibition, antioxidant effects, monoamine-oxidase inhibition, and neuroprotection. Several tryptamine-based hybrid analogs are currently being investigated as multifunctional agents for the development of novel hybrids for AD treatment. Thus, this review article aims to provide in-depth insights into the research progress and strategies for designing multifunctional agents used in Alzheimer's therapy.