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.

Polypharmacology breaks up the classical paradigm of “one-drug, one target, one disease” electing multitarget compounds as potential therapeutic tools suitable for the treatment of complex diseases, such as metabolic syndrome, psychiatric or degenerative central nervous system (CNS) disorders, and cancer. These diseases often require a combination therapy which may result in positive but also negative synergistic effects. The endocannabinoid system (ECS) is emerging as a particularly attractive therapeutic target in CNS disorders and neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, traumatic brain injury (TBI), pain, and epilepsy. ECS is an organized neuromodulatory network, composed by endogenous cannabinoids, cannabinoid receptors type 1 and type 2 (CB1 and CB2), and the main catabolic enzymes involved in the endocannabinoid inactivation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The multiple connections of the ECS with other signaling pathways in the CNS allows the consideration of the ECS as an optimal source of inspiration in the development of innovative polypharmacological compounds. In this review, we focused our attention on the reported polypharmacological examples in which FAAH and MAGL inhibitors are involved.

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.

Adenosine receptors (ARs) have been identified as promising therapeutic targets for countless pathological conditions, spanning from inflammatory diseases to central nervous system disorders, from cancer to metabolic diseases, from cardiovascular pathologies to respiratory diseases, and beyond. This extraordinary therapeutic potential is mainly due to the plurality of pathophysiological actions of adenosine and the ubiquitous expression of its receptors. This is, however, a double-edged sword that makes the clinical development of effective ligands with tolerable side effects difficult. Evidence of this is the low number of AR agonists or antagonists that have reached the market. An alternative approach is to target allosteric sites via allosteric modulators, compounds endowed with several advantages over orthosteric ligands. In addition to the typical advantages of allosteric modulators, those acting on ARs could benefit from the fact that adenosine levels are elevated in pathological tissues, thus potentially having negligible effects on normal tissues where adenosine levels are maintained low. Several A1 and various A3AR allosteric modulators have been identified so far, and some of them have been validated in different preclinical settings, achieving promising results. Less fruitful, instead, has been the discovery of A2A and A2BAR allosteric modulators, although the results obtained up to now are encouraging. Collectively, data in the literature suggests that allosteric modulators of ARs could represent valuable pharmacological tools, potentially able to overcome the limitations of orthosteric ligands.

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The glycogen synthase kinase 3β (GSK‐3β) is a ubiquitous enzyme that is a validated target for the development of potential therapeutics useful in several diseases including retinal degeneration. Aiming at developing an innovative class of allosteric inhibitors of GSK‐3β potentially useful for retinal degeneration, we explored the class of squaramides. The developed compounds (6 a–l) were obtained through a nontoxic one‐pot synthetic protocol, which employs low‐cost goods and avoids any purification step. Ethanol was used as the reaction solvent, simultaneously allowing the pure reaction products′ recovery (by precipitation). Out of this set of squaramides, 6 j stood out, from computational and enzymatic converging data, as an ATP non‐competitive inhibitor of GSK‐3β of micromolar potency. When engaged in cellular studies using retinal pigment epithelial cells (ARPE‐19) transfected with a luciferase reporter gene under the control of T‐cell factor/lymphoid enhancer factor (TCF/LEF) binding sites, 6 j was able to dose‐dependently induce β‐catenin nuclear accumulation, as shown by the increased luciferase activity at a concentration of 2.5 μM.

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.

The Front Cover shows the sustainable approach used to develop new unsymmetrical squaramides acting as allosteric GSK3β inhibitors, promoting TCF‐LEF transcription in retinal pigment epithelial ARPE‐19 cells. This work highlights how green chemistry coupled with computational and biological studies could be a valuable strategy for developing interesting pharmacological tools, activating neuroprotective pathways, and useful in retinal diseases associated with inflammatory/oxidative damage. More information can be found in the Research Article by Gabriele Carullo, Stefania Butini et al.