Binding and unbinding of potent melatonin receptor ligands: Mechanistic simulations and experimental evidence.

The labeled ligand commonly employed in competition binding studies for melatonin receptor ligands, 2-[125I]iodomelatonin, showed slow dissociation with different half-lives at the two receptor subtypes. This may affect the operational measures of affinity constants, which at short incubation times could not be obtained in equilibrium conditions, and structure-activity relationships, as the Ki values of tested ligands could depend on either interaction at the binding site or the dissociation path. To address these issues, the kinetic and saturation binding parameters of 2-[125I]iodomelatonin as well as the competition constants for a series of representative ligands were measured at a short (2 h) and a long (20 h) incubation time. Concurrently, we simulated by molecular modeling the dissociation path of 2-iodomelatonin from MT1 and MT2 receptors and investigated the role of interactions at the binding site on the stereoselectivity observed for the enantiomers of the subtype-selective ligand UCM1014. We found that equilibrium conditions for 2-[125I]iodomelatonin binding can be reached only with long incubation times, particularly for the MT2 receptor subtype, for which a time of 20 h approximates this condition. On the other hand, measured Ki values for a set of ligands including agonists, antagonists, nonselective, and subtype-selective compounds were not significantly affected by the length of incubation, suggesting that structure-activity relationships based on data collected at shorter time reflect different interactions at the binding site. Molecular modeling simulations evidenced that the slower dissociation of 2-iodomelatonin from the MT2 receptor can be related to the restricted mobility of a gatekeeper tyrosine along a lipophilic path from the binding site to the membrane bilayer. The enantiomers of the potent, MT2-selective agonist UCM1014 were separately synthesized and tested. Molecular dynamics simulations of the receptor-ligand complexes provided an explanation for their stereoselectivity as due to the preference shown by the eutomer at the binding site for the most abundant axial conformation adopted by the ligand in solution. These results suggest that, despite the slow-binding kinetics occurring for the labeled ligand, affinity measures at shorter incubation times give robust results consistent with known structure-activity relationships and with interactions taken at the receptor binding site.

Pioneering first-in-class FAAH-HDAC inhibitors as potential multitarget neuroprotective agents.

Aiming to simultaneously modulate the endocannabinoid system (ECS) functions and the epigenetic machinery, we selected the fatty acid amide hydrolase (FAAH) and histone deacetylase (HDAC) enzymes as desired targets to develop potential neuroprotective multitarget-directed ligands (MTDLs), expecting to achieve an additive or synergistic therapeutic effect in oxidative stress-related conditions. We herein report the design, synthesis, and biological evaluation of the first-in-class FAAH-HDAC multitarget inhibitors. A pharmacophore merging strategy was applied, yielding 1-phenylpyrrole-based compounds 4a-j. The best-performing compounds (4c, 4f, and 4h) were tested for their neuroprotective properties in oxidative stress models, employing 1321N1 human astrocytoma cells and SHSY5 human neuronal cells. In our preliminary studies, compound 4h stood out, showing a balanced nanomolar inhibitory activity against the selected targets and outperforming the standard antioxidant N-acetylcysteine in vitro. Together with 4f, 4h was also able to protect 1321N1 cells from tert-butyl hydroperoxide or glutamate insult. Our study may provide the basis for the development of novel MTDLs targeting the ECS and epigenetic enzymes.

Growing up with type 1 diabetes mellitus: Data from the Verona Diabetes Transition Project.

AIM: Transition from paediatric to adult care is a critical step in life of emerging adults with type 1 diabetes. We assessed, according to indicators established by panel of experts, clinical, socio-demographic and psychosocial factors in young adults with type 1 diabetes throughout structured transition to investigate the associations, if any, with HbA1c value at time of transition. METHODS: The "Verona Diabetes Transition Project" started in January 2009: a structured transition program, shared between paediatric and adult clinic, was organised with a multi-disciplinary team. All young adults underwent a semi-structured interview by a psychologist, before transition. Minimum age for transition was 18 years. RESULTS: 222 (M/F = 113/109) young adults moved to adult care from January 2009 to March 2020. The mean time between the last paediatric visit and the first adult visit ranged from 13.6 ± 6.1 months at the beginning of the project to 3.6 ± 11.5 months over the following years. At first adult clinic attendance, women showed higher HbA1c values (70 ± 11 mmol/mol vs. 65 ± 7 mmol/mol or 8.57% ± 1.51% vs. 8.14% ± 0.98%, p = 0.01), higher frequency of disorders of eating behaviours (15.6% vs. 0%, p < 0.001) and poor diabetes acceptance (23.9% vs. 9.7%, p < 0.001) than men. Mediation analyses showed a significant mediating role of glucose control 2 years before transition in the relationship between poor diabetes acceptance and glucose control at transition. CONCLUSIONS: This study demonstrated a delay reduction in establishing care with an adult provider and suggested the potential role of low diabetes acceptance on glycemic control at transition. Further studies are needed to confirm and expand these data.

A2A Adenosine Receptor: A Possible Therapeutic Target for Alzheimer's Disease by Regulating NLRP3 Inflammasome Activity?

The A2A adenosine receptor, a member of the P1 purinergic receptor family, plays a crucial role in the pathophysiology of different neurodegenerative illnesses, including Alzheimer's disease (AD). It regulates both neurons and glial cells, thus modulating synaptic transmission and neuroinflammation. AD is a complex, progressive neurological condition that is the leading cause of dementia in the world's old population (>65 years of age). Amyloid peptide-ß extracellular accumulation and neurofibrillary tangles constitute the principal etiologic tracts, resulting in apoptosis, brain shrinkage, and neuroinflammation. Interestingly, a growing body of evidence suggests a role of NLRP3 inflammasome as a target to treat neurodegenerative diseases. It represents a tripartite multiprotein complex including NLRP3, ASC, and procaspase-1. Its activation requires two steps that lead with IL-1ß and IL-18 release through caspase-1 activation. NLRP3 inhibition provides neuroprotection, and in recent years adenosine, through the A2A receptor, has been reported to modulate NLRP3 functions to reduce organ damage. In this review, we describe the role of NLRP3 in AD pathogenesis, both alone and in connection to A2A receptor regulation, in order to highlight a novel approach to address treatment of AD.

Adenosine Receptors in Neuropsychiatric Disorders: Fine Regulators of Neurotransmission and Potential Therapeutic Targets.

Adenosine exerts an important role in the modulation of central nervous system (CNS) activity. Through the interaction with four G-protein coupled receptor (GPCR) subtypes, adenosine subtly regulates neurotransmission, interfering with the dopaminergic, glutamatergic, noradrenergic, serotoninergic, and endocannabinoid systems. The inhibitory and facilitating actions of adenosine on neurotransmission are mainly mediated by A1 and A2A adenosine receptors (ARs), respectively. Given their role in the CNS, ARs are promising therapeutic targets for neuropsychiatric disorders where altered neurotransmission represents the most likely etiological hypothesis. Activating or blocking ARs with specific pharmacological agents could therefore restore the balance of altered neurotransmitter systems, providing the rationale for the potential treatment of these highly debilitating conditions. In this review, we summarize and discuss the most relevant studies concerning AR modulation in psychotic and mood disorders such as schizophrenia, bipolar disorders, depression, and anxiety, as well as neurodevelopment disorders such as autism spectrum disorder (ASD), fragile X syndrome (FXS), attention-deficit hyperactivity disorder (ADHD), and neuropsychiatric aspects of neurodegenerative disorders.

Pathophysiological Role and Medicinal Chemistry of A2A Adenosine Receptor Antagonists in Alzheimer's Disease.

The A2A adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. It is involved in the regulation of several pathophysiological conditions in both the central nervous system and periphery. In the brain, its localization at pre- and postsynaptic level in striatum, cortex, hippocampus and its effects on glutamate release, microglia and astrocyte activation account for a crucial role in neurodegenerative diseases, including Alzheimer's disease (AD). This ailment is considered the main form of dementia and is expected to exponentially increase in coming years. The pathological tracts of AD include amyloid peptide-ß extracellular accumulation and tau hyperphosphorylation, causing neuronal cell death, cognitive deficit, and memory loss. Interestingly, in vitro and in vivo studies have demonstrated that A2A adenosine receptor antagonists may counteract each of these clinical signs, representing an important new strategy to fight a disease for which unfortunately only symptomatic drugs are available. This review offers a brief overview of the biological effects mediated by A2A adenosine receptors in AD animal and human studies and reports the state of the art of A2A adenosine receptor antagonists currently in clinical trials. As an original approach, it focuses on the crucial role of pharmacokinetics and ability to pass the blood-brain barrier in the discovery of new agents for treating CNS disorders. Considering that A2A receptor antagonist istradefylline is already commercially available for Parkinson's disease treatment, if the proof of concept of these ligands in AD is confirmed and reinforced, it will be easier to offer a new hope for AD patients.

Adenosine and Inflammation: Here, There and Everywhere.

Adenosine is a ubiquitous endogenous modulator with the main function of maintaining cellular and tissue homeostasis in pathological and stress conditions. It exerts its effect through the interaction with four G protein-coupled receptor (GPCR) subtypes referred as A1, A2A, A2B, and A3 adenosine receptors (ARs), each of which has a unique pharmacological profile and tissue distribution. Adenosine is a potent modulator of inflammation, and for this reason the adenosinergic system represents an excellent pharmacological target for the myriad of diseases in which inflammation represents a cause, a pathogenetic mechanism, a consequence, a manifestation, or a protective factor. The omnipresence of ARs in every cell of the immune system as well as in almost all cells in the body represents both an opportunity and an obstacle to the clinical use of AR ligands. This review offers an overview of the cardinal role of adenosine in the modulation of inflammation, showing how the stimulation or blocking of its receptors or agents capable of regulating its extracellular concentration can represent promising therapeutic strategies for the treatment of chronic inflammatory pathologies, neurodegenerative diseases, and cancer.

Pulsed Electromagnetic Field Stimulation in Osteogenesis and Chondrogenesis: Signaling Pathways and Therapeutic Implications.

Mesenchymal stem cells (MSCs) are the main cell players in tissue repair and thanks to their self-renewal and multi-lineage differentiation capabilities, they gained significant attention as cell source for tissue engineering (TE) approaches aimed at restoring bone and cartilage defects. Despite significant progress, their therapeutic application remains debated: the TE construct often fails to completely restore the biomechanical properties of the native tissue, leading to poor clinical outcomes in the long term. Pulsed electromagnetic fields (PEMFs) are currently used as a safe and non-invasive treatment to enhance bone healing and to provide joint protection. PEMFs enhance both osteogenic and chondrogenic differentiation of MSCs. Here, we provide extensive review of the signaling pathways modulated by PEMFs during MSCs osteogenic and chondrogenic differentiation. Particular attention has been given to the PEMF-mediated activation of the adenosine signaling and their regulation of the inflammatory response as key player in TE approaches. Overall, the application of PEMFs in tissue repair is foreseen: (1) in vitro: to improve the functional and mechanical properties of the engineered construct; (2) in vivo: (i) to favor graft integration, (ii) to control the local inflammatory response, and (iii) to foster tissue repair from both implanted and resident MSCs cells.

Structural investigation on thiazolo[5,4-d]pyrimidines to obtain dual-acting blockers of CD73 and adenosine A2A receptor as potential antitumor agents.

Adenosine pathway, including its generating enzyme (CD73) and its receptors represents a key target for cancer immunotherapy. Here we aimed to search for novel compounds able to co-target the CD73 and the A2A adenosine receptor (A2A AR) as dual-blockers of adenosine generation and activity. The design project was to combine in the same molecule the thiazolo[5,4-d]pyrimidine core, an essential pharmacophoric feature to block the A2A AR, with a benzenesulfonamide group which is a characteristic group of CD73 inhibitors. Most of the reported compounds resulted in inverse agonists of the human (h) A2A AR endowed with high affinity, selectivity and potency. However they were weak inhibitors of CD73 enzyme. Nevertheless, this study can be considered as a starting point to develop more active compounds.

Targeting Adenosine Receptors: A Potential Pharmacological Avenue for Acute and Chronic Pain.

Adenosine is a purine nucleoside, responsible for the regulation of multiple physiological and pathological cellular and tissue functions by activation of four G protein-coupled receptors (GPCR), namely A1, A2A, A2B, and A3 adenosine receptors (ARs). In recent years, extensive progress has been made to elucidate the role of adenosine in pain regulation. Most of the antinociceptive effects of adenosine are dependent upon A1AR activation located at peripheral, spinal, and supraspinal sites. The role of A2AAR and A2BAR is more controversial since their activation has both pro- and anti-nociceptive effects. A3AR agonists are emerging as promising candidates for neuropathic pain. Although their therapeutic potential has been demonstrated in diverse preclinical studies, no AR ligands have so far reached the market. To date, novel pharmacological approaches such as adenosine regulating agents and allosteric modulators have been proposed to improve efficacy and limit side effects enhancing the effect of endogenous adenosine. This review aims to provide an overview of the therapeutic potential of ligands interacting with ARs and the adenosinergic system for the treatment of acute and chronic pain.

Pulsed Electromagnetic Fields Stimulate HIF-1α-Independent VEGF Release in 1321N1 Human Astrocytes Protecting Neuron-Like SH-SY5Y Cells from Oxygen-Glucose Deprivation.

Pulsed electromagnetic fields (PEMFs) are emerging as an innovative, non-invasive therapeutic option in different pathological conditions of the central nervous system, including cerebral ischemia. This study aimed to investigate the mechanism of action of PEMFs in an in vitro model of human astrocytes, which play a key role in the events that occur following ischemia. 1321N1 cells were exposed to PEMFs or hypoxic conditions and the release of relevant neurotrophic and angiogenic factors, such as VEGF, EPO, and TGF-ß1, was evaluated by means of ELISA or AlphaLISA assays. The involvement of the transcription factor HIF-1α was studied by using the specific inhibitor chetomin and its expression was measured by flow cytometry. PEMF exposure induced a time-dependent, HIF-1α-independent release of VEGF from 1321N1 cells. Astrocyte conditioned medium derived from PEMF-exposed astrocytes significantly reduced the oxygen-glucose deprivation-induced cell proliferation and viability decrease in the neuron-like cells SH-SY5Y. These findings contribute to our understanding of PEMFs action in neuropathological conditions and further corroborate their therapeutic potential in cerebral ischemia.

Development of novel pyridazinone-based adenosine receptor ligands.

With the aim of finding new adenosine receptor (AR) ligands, a preliminary investigation focusing on the thieno[2,3-d]pyridazin-5(4H)-one scaffold was undertaken. The synthesized compounds 1-11 were evaluated for their binding at hA1, hA2A and hA3 ARs and efficacy at hA2B subtype in order to determine the affinity at the human adenosine receptor subtypes. Small structural changes on this scaffold highly influenced affinity; compound 5 (5-ethyl-7-(thiazol-2-yl)thieno[2,3-d]pyridazin-4(5H)-one) emerged as the best of this series. The simplicity of the synthetic process, the capability of the scaffold to be easily decorated, together with the predicted ADME properties confirm the role of these compounds as promising hits. A molecular docking investigation at the hA1AR crystal structure was performed to rationalize the SARs of the herein reported thienopyridazinones.

Identification of novel thiazolo[5,4-d]pyrimidine derivatives as human A1 and A2A adenosine receptor antagonists/inverse agonists.

In this study a new set of thiazolo[5,4-d]pyrimidine derivatives was synthesized. These derivatives bear different substituents at positions 2 and 5 of the thiazolopyrimidine core while maintaining a free amino group at position-7. The new compounds were tested for their affinity and potency at human (h) A1, A2A, A2B and A3 adenosine receptors expressed in CHO cells. The results reveal that the higher affinity of these new set of thiazolopyrimidines is toward the hA1 and hA2A adenosine receptors subtypes and is tuned by the substitution pattern at both the 2 and 5 positions of the thiazolopyrimidine nucleus. Functional studies evidenced that the compounds behaved as dual A1/A2A antagonists/inverse agonists. Compound 3, bearing a 5-((2-methoxyphenyl) methylamino) group and a phenyl moiety at position 2, displayed the highest affinity (hA1 Ki = 10.2 nM; hA2A Ki = 4.72 nM) and behaved as a potent A1/A2A antagonist/inverse agonist (hA1 IC50 = 13.4 nM; hA2A IC50 = 5.34 nM).

Pulsed Electromagnetic Field Exposure Reduces Hypoxia and Inflammation Damage in Neuron-Like and Microglial Cells.

In the present study, the effect of low-frequency, low-energy pulsed electromagnetic fields (PEMFs) has been investigated by using different cell lines derived from neuron-like cells and microglial cells. In particular, the primary aim was to evaluate the effect of PEMF exposure in inflammation- and hypoxia-induced injury in two different neuronal cell models, the human neuroblastoma-derived SH-SY5Y cells and rat pheochromocytoma PC12 cells and in N9 microglial cells. In neuron-like cells, live/dead and apoptosis assays were performed in hypoxia conditions from 2 to 48 h. Interestingly, PEMF exposure counteracted hypoxia damage significantly reducing cell death and apoptosis. In the same cell lines, PEMFs inhibited the activation of the hypoxia-inducible factor 1α (HIF-1α), the master transcriptional regulator of cellular response to hypoxia. The effect of PEMF exposure on reactive oxygen species (ROS) production in both neuron-like and microglial cells was investigated considering their key role in ischemic injury. PEMFs significantly decreased hypoxia-induced ROS generation in PC12, SH-SY5Y, and N9 cells after 24 or 48 h of incubation. Moreover, PEMFs were able to reduce some of the most well-known pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, and IL-8 release in N9 microglial cells stimulated with different concentrations of LPS for 24 or 48 h of incubation time. These results show a protective effect of PEMFs on hypoxia damage in neuron-like cells and an anti-inflammatory effect in microglial cells suggesting that PEMFs could represent a potential therapeutic approach in cerebral ischemic conditions. J. Cell. Physiol. 232: 1200-1208, 2017. © 2016 Wiley Periodicals, Inc.

Adenosine Receptors as a Biological Pathway for the Anti-Inflammatory and Beneficial Effects of Low Frequency Low Energy Pulsed Electromagnetic Fields.

Several studies explored the biological effects of low frequency low energy pulsed electromagnetic fields (PEMFs) on human body reporting different functional changes. Much research activity has focused on the mechanisms of interaction between PEMFs and membrane receptors such as the involvement of adenosine receptors (ARs). In particular, PEMF exposure mediates a significant upregulation of A2A and A3ARs expressed in various cells or tissues involving a reduction in most of the proinflammatory cytokines. Of particular interest is the observation that PEMFs, acting as modulators of adenosine, are able to increase the functionality of the endogenous agonist. By reviewing the scientific literature on joint cells, a double role for PEMFs could be hypothesized in vitro by stimulating cell proliferation, colonization of the scaffold, and production of tissue matrix. Another effect could be obtained in vivo after surgical implantation of the construct by favoring the anabolic activities of the implanted cells and surrounding tissues and protecting the construct from the catabolic effects of the inflammatory status. Moreover, a protective involvement of PEMFs on hypoxia damage in neuron-like cells and an anti-inflammatory effect in microglial cells have suggested the hypothesis of a positive impact of this noninvasive biophysical stimulus.

The role of 5-arylalkylamino- and 5-piperazino- moieties on the 7-aminopyrazolo[4,3-d]pyrimidine core in affecting adenosine A1 and A2A receptor affinity and selectivity profiles.

New 7-amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives, substituted at the 5-position with aryl(alkyl)amino- and 4-substituted-piperazin-1-yl- moieties, were synthesized with the aim of targeting human (h) adenosine A1 and/or A2A receptor subtypes. On the whole, the novel derivatives 1-24 shared scarce or no affinities for the off-target hA2B and hA3 ARs. The 5-(4-hydroxyphenethylamino)- derivative 12 showed both good affinity (Ki = 150 nM) and the best selectivity for the hA2A AR while the 5-benzylamino-substituted 5 displayed the best combined hA2A (Ki = 123 nM) and A1 AR affinity (Ki = 25 nM). The 5-phenethylamino moiety (compound 6) achieved nanomolar affinity (Ki = 11 nM) and good selectivity for the hA1 AR. The 5-(N4-substituted-piperazin-1-yl) derivatives 15-24 bind the hA1 AR subtype with affinities falling in the high nanomolar range. A structure-based molecular modeling study was conducted to rationalize the experimental binding data from a molecular point of view using both molecular docking studies and Interaction Energy Fingerprints (IEFs) analysis.[Formula: see text].

Role and Function of A2A and A3 Adenosine Receptors in Patients with Ankylosing Spondylitis, Psoriatic Arthritis and Rheumatoid Arthritis.

Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are chronic inflammatory rheumatic diseases that affect joints, causing debilitating pain and disability. Adenosine receptors (ARs) play a key role in the mechanism of inflammation, and the activation of A2A and A3AR subtypes is often associated with a reduction of the inflammatory status. The aim of this study was to investigate the involvement of ARs in patients suffering from early-RA (ERA), RA, AS and PsA. Messenger RNA (mRNA) analysis and saturation binding experiments indicated an upregulation of A2A and A3ARs in lymphocytes obtained from patients when compared with healthy subjects. A2A and A3AR agonists inhibited nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation and reduced inflammatory cytokines release, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-6. Moreover, A2A and A3AR activation mediated a reduction of metalloproteinases (MMP)-1 and MMP-3. The effect of the agonists was abrogated by selective antagonists demonstrating the direct involvement of these receptor subtypes. Taken together, these data confirmed the involvement of ARs in chronic autoimmune rheumatic diseases highlighting the possibility to exploit A2A and A3ARs as therapeutic targets, with the aim to limit the inflammatory responses usually associated with RA, AS and PsA.

A novel potent class I HDAC inhibitor reverses the STAT4/p66Shc apoptotic defect in B cells from chronic lymphocytic leukemia patients.

Chronic Lymphocytic Leukemia (CLL) patients have a defective expression of the proapoptotic protein p66Shc and of its transcriptional factor STAT4, which evoke molecular abnormalities, impairing apoptosis and worsening disease prognosis and severity. p66Shc expression is epigenetically controlled and transcriptionally modulated by STAT4; epigenetic modifiers are deregulated in CLL cells and specific histone deacetylases (HDACs) like HDAC1, are overexpressed. Reactivation of STAT4/p66Shc expression may represent an attractive and challenging strategy to reverse CLL apoptosis defects. New selective class I HDAC inhibitors (HDACis, 6a-g) were developed with increased potency over existing agents and preferentially interfering with the CLL-relevant isoform HDAC1, to unveil the role of class I HDACs in the upregulation of STAT4 expression, which upregulates p66Shc expression and hence normalizes CLL cell apoptosis. 6c (chlopynostat) was identified as a potent HDAC1i with a superior profile over entinostat. 6c induces marked apoptosis of CLL cells compared with SAHA, which was associated with an upregulation of STAT4/p66Shc protein expression. The role of HDAC1, but not HDAC3, in the epigenetic upregulation of STAT4/p66Shc was demonstrated for the first time in CLL cells and was validated in siRNA-induced HDAC1/HDAC3 knock-down EBV-B cells. To sum up, HDAC1 inhibition is necessary to reactivate STAT4/p66Shc expression in patients with CLL. 6c is one of the most potent HDAC1is known to date and represents a novel pharmacological tool for reversing the impairment of the STAT4/p66Shc apoptotic machinery.

Are Two Riboses Better Than One? The Case of the Recognition and Activation of Adenosine Receptors.

Traditionally, molecular recognition between the orthosteric site of adenosine receptors and their endogenous ligand occurs with a 1 : 1 stoichiometry. Inspired by previous mechanistic insights derived from supervised molecular dynamics (SuMD) simulations, which suggested an alternative 2 : 1 binding stoichiometry, we synthesized BRA1, a bis-ribosyl adenosine derivative, tested its ability to bind to and activate members of the adenosine receptor family, and rationalized its activity through molecular modeling.

Caffeine for Prevention of Alzheimer's Disease: Is the A2A Adenosine Receptor Its Target?

Alzheimer's disease (AD) is the most prevalent kind of dementia with roughly 135 million cases expected in the world by 2050. Unfortunately, current medications for the treatment of AD can only relieve symptoms but they do not act as disease-modifying agents that can stop the course of AD. Caffeine is one of the most widely used drugs in the world today, and a number of clinical studies suggest that drinking coffee may be good for health, especially in the fight against neurodegenerative conditions such as AD. Experimental works conducted "in vivo" and "in vitro" provide intriguing evidence that caffeine exerts its neuroprotective effects by antagonistically binding to A2A receptors (A2ARs), a subset of GPCRs that are triggered by the endogenous nucleoside adenosine. This review provides a summary of the scientific data supporting the critical role that A2ARs play in memory loss and cognitive decline, as well as the evidence supporting the protective benefits against neurodegeneration that may be attained by caffeine's antagonistic action on these receptors. They are a novel and fascinating target for regulating and enhancing synaptic activity, achieving symptomatic and potentially disease-modifying effects, and protecting against neurodegeneration.