A2A Adenosine Receptor Antagonists in Neurodegenerative Diseases

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.

Keywords: A_2A antagonists; A_2A receptors; Alzheimer’s disease; cognitive impairment; drug design; neuroinflammation.