Abstract
BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia worldwide, with approximately 6 million cases reported in America in 2020. The clinical signs of AD include cognitive dysfunction, apathy, anxiety and neuropsychiatric signs, and pathogenetic mechanisms that involve amyloid peptide-β extracellular accumulation and tau hyperphosphorylation. Unfortunately, current drugs to treat AD can provide only symptomatic relief but are not disease-modifying molecules able to revert AD progression. The endogenous modulator adenosine, through A(2A) receptor activation, plays a role in synaptic loss and neuroinflammation, which are crucial for cognitive impairment and memory damage. OBJECTIVE: In this review, recent advances covering A(2A) adenosine receptor antagonists will be extensively reviewed, providing a basis for the rational design of future A(2A) inhibitors. METHODS: Herein, the literature on A(2A) adenosine receptors and their role in synaptic plasticity and neuroinflammation, as well as the effects of A(2A) antagonism in animal models of AD and in humans, are reviewed. Furthermore, current chemical and structure-based strategies are presented. RESULTS: Caffeine, the most widely consumed natural product stimulant and an A(2A) antagonist, improves human memory. Similarly, synthetic A(2A) receptor antagonists, as described in this review, may provide a means to fight AD. CONCLUSION: This review highlights the clinical potential of A(2A) adenosine receptor antagonists as a novel approach to treat patients with AD.