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-ß 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.
Subject(s)
Alzheimer Disease , Neurodegenerative Diseases , Adenosine A2 Receptor Antagonists/pharmacology , Adenosine A2 Receptor Antagonists/therapeutic use , Alzheimer Disease/drug therapy , Amyloid beta-Peptides , Animals , Caffeine/therapeutic use , Humans , Neurodegenerative Diseases/drug therapy , Purinergic P1 Receptor Antagonists/therapeutic use , Receptor, Adenosine A2AABSTRACT
The adenosine receptors (A(1), A(2A), A(2B) and A(3)) are important and ubiquitous mediators of cellular signalling, which play vital roles in protecting tissues and organs from damage. Launched drugs include the adenosine receptor antagonists theophylline and doxofylline (both used as bronchodilators in respiratory disorders such as asthma), while several compounds are presently in clinical trials for a range of indications, including heart failure, Parkinson's disease, rheumatoid arthritis, cancer, pain and chronic obstructive pulmonary disease. A host of companies and institutions are addressing the huge potential for the development of selective adenosine receptor agonists and antagonists, so that it appears we are on the verge of a new wave of compounds approaching the market for many unmet medical needs. This review presents an analysis of the patenting activity in the area for 2006 and an interpretation and reflection on the developments that we can expect in the future.
