Stefania Merighi*, Pier A. Borea, Katia Varani, Fabrizio Vincenzi, Kenneth A. Jacobson* and Stefania Gessi* Pages 4138 - 4151 ( 14 )
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 A2A 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 A2A adenosine receptor antagonists will be extensively reviewed, providing a basis for the rational design of future A2A inhibitors.
Methods: Herein, the literature on A2A adenosine receptors and their role in synaptic plasticity and neuroinflammation, as well as the effects of A2A 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 A2A antagonist, improves human memory. Similarly, synthetic A2A receptor antagonists, as described in this review, may provide a means to fight AD.
Conclusion: This review highlights the clinical potential of A2A adenosine receptor antagonists as a novel approach to treat patients with AD.
Alzheimer’s disease, A<sub>2A</sub> receptors, A<sub>2A</sub> antagonists, cognitive impairment, drug design, neuroinflammation.
Department of Translational Medicine and for Romagna, University of Ferrara, 44121, Ferrara, University of Ferrara, 44121, Ferrara, Department of Translational Medicine and for Romagna, University of Ferrara, 44121, Ferrara, Department of Translational Medicine and for Romagna, University of Ferrara, 44121, Ferrara, Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, Department of Translational Medicine and for Romagna, University of Ferrara, 44121, Ferrara