A_2A Adenosine Receptor Antagonists in Neurodegenerative Diseases

Title:A_2A Adenosine Receptor Antagonists in Neurodegenerative Diseases

Volume: 29 Issue: 24

Author(s): Stefania Merighi*, Pier A. Borea, Katia Varani, Fabrizio Vincenzi, Kenneth A. Jacobson*Stefania Gessi*

Affiliation:

• Department of Translational Medicine and for Romagna, University of Ferrara, 44121, Ferrara, Italy

• Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA

• Department of Translational Medicine and for Romagna, University of Ferrara, 44121, Ferrara, Italy

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

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.

Cite this article as:

Merighi Stefania *, Borea A. Pier, Varani Katia , Vincenzi Fabrizio , Jacobson A. Kenneth *, Gessi Stefania *, A_2A Adenosine Receptor Antagonists in Neurodegenerative Diseases, Current Medicinal Chemistry 2022; 29 (24) . https://dx.doi.org/10.2174/0929867328666211129122550