Abstract
The therapeutic potential of targeting adenosine A2A receptors (A2ARs) is immense due to their broad expression in the body and central nervous system. The role of A2ARs in cardiovascular function, inflammation, sleep/wake behaviors, cognition, and other primary nervous system functions has been extensively studied. Numerous A2AR agonist and antagonist molecules are reported, many of which are currently in clinical trials or have already been approved for treatment. Allosteric modulators can selectively elicit a physiologic response only where and when the orthosteric ligand is released, which reduces the risk of an adverse effect resulting from A2AR activation. Thus, these allosteric modulators have a potential therapeutic advantage over classical agonist and antagonist molecules. This review focuses on the recent developments regarding allosteric A2AR modulation, which is a promising area for future pharmaceutical research because the list of existing allosteric A2AR modulators and their physiologic effects is still short.
Highlights
Adenosine is a naturally occurring purine nucleoside that regulates various physiologic functions, including inflammation and wound healing, cardiac contraction, blood vessel formation, vasodilation, learning, memory, sleep, and arousal [1–7]
This review focuses on allosteric A2A receptors (A2A Rs) modulation and the latest developments in this emerging field
Rs enhances the activation of cyclic adenosine phosphate and protein kinase A (PKA), 2A
Summary
Adenosine is a naturally occurring purine nucleoside that regulates various physiologic functions, including inflammation and wound healing, cardiac contraction, blood vessel formation, vasodilation, learning, memory, sleep, and arousal [1–7]. Extracellular adenosine modulates neuronal excitability, synaptic plasticity, and the release and reuptake of several neurotransmitters [9–12]. Adenosine A2A receptors (A2A Rs) are broadly expressed in the brain, cardiovascular system, blood vessels, spleen, thymus, leukocytes, and lung, making them an important drug target [14]. The therapeutic potential of targeting A2A Rs has prompted the development of numerous antagonist and agonist molecules to selectively control A2A R function. A2A R agonists and antagonists are considered potential therapeutic agents for inflammation, sickle cell disease, ischemia-reperfusion injury, and central nervous system (CNS). Unlike agonist and antagonist molecules, allosteric modulators evoke a selective physiologic response only where and when the orthosteric ligand is released [17]. The list of existing allosteric A2A R modulators is short, and the physiologic opportunities for modulators are just emerging, making allosteric A2A R modulation a promising area for future research
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