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Pier Borea

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PhD in Chemistry, Full Professor of Pharmacology, School of Medicine, University of Ferrara, Italy ( 1994) . Olim Chairman of the Department of Clinical and Experimental Medicine, Olim president of the Italian Chapter of Purine Club, Olim Coordinator of the PhD Program in Molecular and Cellular Pharmacology, Honorary Professor of Pharmacology in the School of Medicine, University of Ferrara. Coauthor of some 400 full papers, 25 patents. 30 book chapters, Editor or coeditor of books, total impact factor of about 1400, H factor ( Google Scholar) 57, total citations (Google Scholar) more than 10,000. Chairman or coChairman of National and International Symposia.

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Universidade de Vigo

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UCLouvain (University of Louvain)

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Papers by Pier Borea

Pyrazolo [4,3-E]1,2,4-triazolo[1,5-c]pyrimidine derivates a new class of potent and selective human A3 adenosine receptor antagonists

Drug Development Research, 2000

ABSTRACT

An Open Question: Is the A2A Adenosine Receptor a Novel Target for Alzheimer’s Disease Treatment?

Frontiers in Pharmacology, Mar 22, 2021

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

International Journal of Molecular Sciences, May 2, 2022

The A 2A adenosine receptor, a member of the P1 purinergic receptor family, plays a crucial role ... more The A 2A 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-β 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-1β and IL-18 release through caspase-1 activation. NLRP3 inhibition provides neuroprotection, and in recent years adenosine, through the A 2A 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 A 2A 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

International Journal of Molecular Sciences, Jan 22, 2022

Adenosine exerts an important role in the modulation of central nervous system (CNS) activity. Th... more 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 A 1 and A 2A 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.

Targeting A3 and A2A adenosine receptors in the fight against cancer

Expert Opinion on Therapeutic Targets, Jun 12, 2019

-Adenosine is an endogenous and ubiquitous nucleoside, deriving from dephosphorylation of both in... more -Adenosine is an endogenous and ubiquitous nucleoside, deriving from dephosphorylation of both intracellular and extracellular ATP, rising under stressed conditions present in several pathologies and acting through interaction with four GPCR receptors, named A1, A2A, A2B and A3. -Adenosine plays a crucial role in the regulation of cancer cell biology by regulating both tumor and immune cells, through interaction with its cognate A3 and A2A receptors, respectively. Specifically, a vicious cycle of tumor hypoxia, increased adenosine concentrations, immune suppression and cancer growth implies the use of adenosine receptor ligands in tumors. -Highly selective A3 agonists with potential as anticancer drugs have been developed, exploiting their anti-proliferative and proapoptotic effects. These ligands represent a new and original anticancer approach, addressing for the first time both cancer and healthy immune cells. -A3 receptors are overexpressed in almost all cancer types, indicating that A3 agonists could offer the opportunity of an innovative personalized cancer therapy. The A3 receptor represents an effective tumor biomarker, being its overexpression at baseline in correlation with a positive response in patients. -Potent and selective A2A receptor antagonists have been developed based on the awareness that hypoxic generation of adenosine in tumors is crucial for their immuno-escape A2A receptorsmediated. Based on the ability of these compounds to activate the immune system, clinical trials have been designed to evaluate their antitumor efficacy in combination with immunological drugs. -The A3 agonist Namodenoson, as well as A2A antagonists Preladenant, PBF-509, CPI-444 and AZD4635, in clinical development, demonstrate a good safety profile, no side effects, and an acceptable pharmacokinetic behavior, thereby giving hope for the future for a new generation of drugs capable of changing the fate of numerous types of tumor.

Design, Synthesis, and Pharmacological Characterization of 2-(2-Furanyl)thiazolo[5,4-<i>d</i>]pyrimidine-5,7-diamine Derivatives: New Highly Potent A<sub>2A</sub> Adenosine Receptor Inverse Agonists with Antinociceptive Activity

Journal of Medicinal Chemistry, Nov 29, 2016

In this study, we describe the design and synthesis of new N 5 -substituted-2-(2-furanyl) thiazol... more In this study, we describe the design and synthesis of new N 5 -substituted-2-(2-furanyl) thiazolo [5,4-d]pyrimidine-5,7-diamines (2-18) and their pharmacological characterization as A2A adenosine receptor (AR) antagonists by using in vitro and in vivo assays. In competition binding experiments two derivatives (13 and 14) emerged as outstanding ligands showing two different affinity values (KH and KL) for the hA2A receptor with the high affinity KH value in the femtomolar range. The in vitro functional activity assays, performed by using cyclic AMP experiments, assessed that they behave as potent inverse agonists at the hA2A AR. Compounds 13 and 14 were evaluated for their antinociceptive activity in acute experimental models of pain showing an effect equal to or greater than that of morphine. Overall, these novel inverse agonists might represent potential drug candidates for an alternative approach to the management of pain.

Synthesis and biological evaluation of a new series of 2-amino-3-aroyl thiophene derivatives as agonist allosteric modulators of the A 1 adenosine receptor. A position-dependent effect study

European journal of medicinal chemistry, Aug 1, 2015

The 2-amino-3-(p-chlorobenzoyl)thiophene scaffold has been widely employed as a pharmacophore for... more The 2-amino-3-(p-chlorobenzoyl)thiophene scaffold has been widely employed as a pharmacophore for the identification of small molecules acting as allosteric modulators at the adenosine A 1 receptor. A new series of 2-amino-3-(p-chlorobenzoyl)-4-benzyl-5-arylthiophene derivatives, characterized by the absence as well as the presence of electron-releasing or electronwithdrawing groups on the phenyl ring at the 4-and 5-positions of the thiophene ring, were identified as positive allosteric enhancers at the adenosine A 1 receptor in binding (saturation, competition and dissociation kinetics) and functional assays. To better understand the positional requirements of substituents on the 2-amino-3-(p-chlorobenzoyl)thiophene core, the corresponding regioisomeric 4-aryl-5-benzylthiophene analogues were synthesized and found to possess reduced allosteric enhancer activity.

Adenosine Receptors and Cancer

Handbook of experimental pharmacology, 2009

The A 1 , A 2A , A 2B and A 3 G-protein-coupled cell surface adenosine receptors (ARs) are found ... more The A 1 , A 2A , A 2B and A 3 G-protein-coupled cell surface adenosine receptors (ARs) are found to be upregulated in various tumor cells. Activation of the receptors by specific ligands, agonists or antagonists, modulates tumor growth via a range of signaling pathways. The A 1 AR was found to play a role in preventing the development of glioblastomas. This antitumor effect of the A 1 AR is mediated via tumor-associated microglial cells. Activation of the A 2A AR results in inhibition of the immune response to tumors via suppression of T regulatory cell function and inhibition of natural killer cell cytotoxicity and tumor-specific CD4+/CD8+ activity. Therefore, it is suggested that pharmacological inhibition by specific antagonists may enhance immunotherapeutics in cancer therapy. Activation of the A 2B AR plays a role in the development of tumors via upregulation of the expression levels of angiogenic factors in microvascular endothelial cells. In contrast, it was evident that activation of A 2B AR results in inhibition of ERK1/2 phosphorylation and MAP kinase activity, which are involved in tumor cell growth signals. Finally, A 3 AR was found to be highly expressed in tumor cells and tissues while low expression levels were noted in normal cells or adjacent tissue. Receptor expression in the tumor tissues was directly correlated to disease severity. The high receptor expression in the tumors was attributed to overexpression of NF-κB, known to act as an A 3 AR transcription factor. Interestingly, high A 3 AR expression levels were found in peripheral blood mononuclear cells (PBMCs) derived from tumor-bearing animals and cancer patients, reflecting receptor status in the tumors. A 3 AR agonists were found to induce tumor growth inhibition, both in vitro and in vivo, via modulation of the Wnt and the NF-κB signaling pathways. Taken together, A 3 ARs that are abundantly expressed in tumor cells may be targeted by specific A 3 AR agonists, leading to tumor growth inhibition. The unique characteristics of these A 3 AR agonists make them attractive as drug candidates.

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

Molecules, Apr 21, 2022

The A 2A adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. ... more The A 2A 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-β extracellular accumulation and tau hyperphosphorylation, causing neuronal cell death, cognitive deficit, and memory loss. Interestingly, in vitro and in vivo studies have demonstrated that A 2A 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 A 2A adenosine receptors in AD animal and human studies and reports the state of the art of A 2A 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 A 2A 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.

Pharmacological characterization ofalpha2-adrenoceptors in human cerebral cortex and platelets

Deregulation of Adenosine Receptors in Psoriatic Epidermis: An Option for Therapeutic Treatment

Journal of Investigative Dermatology, 2017

Comparative molecular field analysis (CoMFA) of a series of selective adenosine receptor A2A antagonists

Drug Development Research, Feb 1, 1999

ABSTRACT

Preparation of sulfonamido nucleosides as human adenosine A3 receptro agonists and antitumor agents

The invention realizes that a series of sulfonamido derivs. I, wherein wherein Ar is an aryl grou... more The invention realizes that a series of sulfonamido derivs. I, wherein wherein Ar is an aryl group; and R and R1 are independently H, alkyl, aryl, heteroaryl, alkenyl, cycloalkenyl, cycloalkyl, alkoxy, alkynyl, and where taken together R and R1 may form a or carbocyclic or heterocyclic fused ring system which includes both alicyclic and arom. structures with a conserved uronamide group at the 5' position provide superior A3 receptor affinity as well as selectivity. These new adenosine agonists are sulfonamido derivs. N-substituted with aliph. groups (cyclic or linear) or arom. radicals. Mediation of the A3 receptor has been found to induce behavioral depression and protect against cerebral ischemia, and to induce apoptosis in HL-60 human leukemia cells. The A3 adenosine receptor is known to mediate many processes, such as inflammation, hypotension, and mast cell deregulation. These compds. can be used to treat cancer. This particularly includes cancers that express elevated levels of A3 receptors. This would include, but not be limited to, ovarian cancer, breast cancer, colon cancer, and melanoma. Thus, nucleoside II was prepd. and tested in vitro as adenosine A3 receptor agonist and antitumor agent

M3 muscarinic receptors in peripheral lung parenchima of patients with chronic obstructive pulmonary disease

Adenosine in a Human Model of Hypoxic Foam Cells

Foam cells formation by oxidized low-density lipoprotein (oxLDL) accumulation in macrophages is c... more Foam cells formation by oxidized low-density lipoprotein (oxLDL) accumulation in macrophages is crucial for development of atherosclerosis. Macrophage foam cell formation is an important process in atherosclerotic plaque development.1 Atherosclerosis is initiated by dysfunction of endothelial cells at lesion-prone sites in the walls of arteries, which results in monocyte infiltration into the arterial intima. These cells differentiated into macrophages, which then internalize large amounts of oxidized low-density lipoprotein forming cholesterol-laden macrophages called “foam cells”, which in turn give rise to fatty streaks in the arterial wall. As the atherosclerotic lesion develops, the arterial wall tickness increases and oxygen diffusion into the intima is markedly reduced.2 These hypoxic regions contain large number of foam cells revealing that these cells experience hypoxia during the development of atherosclerotic lesions. Hypoxia has been demonstrated in atherosclerosis and hypoxia-inducible factor-1 (HIF-1) has been shown to promote intraplaque angiogenesis and foam cells development. Adenosine is a proangiogenic purine nucleoside released from ischemic and hypoxic tissues. In this study we found that Adenosine, under hypoxia, stimulates HIF-1α accumulation by activating adenosine receptors. This study provides the first evidence that adenosine antagonists may be useful to block important steps in the atherosclerotic plaque development ado-induced. (1) Lusis, AJ. Atherosclerosis. Nature. 2000, 407, 233-241. (2) Björnheden, T.; Levin, M.; Evaldsson, M.; Wiklund, O. Evidence of hypoxic areas within the arterial wall in vivo. Arterioscler. Thromb. Vasc. Biol. 1999, 19, 870-876

Effect of chronic caffeine intake on A2A adenosine receptors in human neutrophils

Pharmacological characterization of purine receptors in bovine fibroblast-like synoviocytes

Growing evidence also suggests that extracellular nucleotides, acting through purinergic receptor... more Growing evidence also suggests that extracellular nucleotides, acting through purinergic receptors, play a central role in the regulation of bone and cartilage metabolism. Fibroblast-like synoviocytes are closely involved in the pathogenesis of joint destruction by an increased proliferation and by the secretion of a wide range of pro-inflammatory mediators including cytokines, growth factors and lipid mediators. The aim of the present study was to investigate from a biochemical, physico chemical and functional point of view A1, A2A, A2B and A3 adenosine receptors and P2X1 and P2X3 purinergic receptors in bovine fibroblast-like synoviocytes. Saturation binding experiments on purine receptors in bovine fibroblast-like synoviocytes were performed and demonstrated the presence of all the adenosine receptors and P2X1 and P2X3 purinergic subtypes. The affinity of typical adenosine and purinergic ligands were studied through competition binding experiments. Thermodynamic analysis of the binding of purine receptors was studied to investigate the forces driving drug-receptor coupling and to verify if adenosine and purinergic ligands were thermodynamically discriminated. The potency of typical purine agonists and antagonists was evaluated in different functional assays such as intracellular cyclic AMP accumulation, PGE2 release and NO production. In particular, A2A but not A3 agonists were involved in the negative modulation of PGE2 synthesis confirming the anti-inflammatory role of the A2A receptors. Well-known purinergic agonists were able to increase NO and PGE2 production suggesting that the stimulation of purinergic receptors increase the inflammation processes

Adenosine A2A receptors of human circulating blood elements

Drug Development Research, Nov 1, 1998

ABSTRACT

Adenosinergic System Involvement in Ischemic Stroke Patients’ Lymphocytes

Cells, Apr 25, 2020

Adenosine modulates many physiological processes through the interaction with adenosine receptors... more Adenosine modulates many physiological processes through the interaction with adenosine receptors (ARs) named as A 1 , A 2A , A 2B, and A 3 ARs. During ischemic stroke, adenosine mediates neuroprotective and anti-inflammatory effects through ARs activation. One of the dominant pathways generating extracellular adenosine involves the dephosphorylation of ATP by ecto-nucleotidases CD39 and CD73, which efficiently hydrolyze extracellular ATP to adenosine. The aim of the study is to assess the presence of ARs in lymphocytes from ischemic stroke patients compared to healthy subjects and to analyze changes in CD39 and CD73 expression in CD4 + and CD8 + lymphocytes. Saturation binding experiments revealed that A 2A ARs affinity and density were significantly increased in ischemic stroke patients whilst no differences were found in A 1 , A 2B, and A 3 ARs. These results were also confirmed in reverse transcription (RT)-polymerase chain reaction (PCR) assays where A 2A AR mRNA levels of ischemic stroke patients were higher than in control subjects. In flow cytometry experiments, the percentage of CD73 + cells was significantly decreased in lymphocytes and in T-lymphocyte subclasses CD4 + and CD8 + obtained from ischemic stroke patients in comparison with healthy individuals. These data corroborate the importance of the adenosinergic system in ischemic stroke and could open the way to more targeted therapeutic approaches and biomarker development for ischemic stroke.

A2A Adenosine Receptor Antagonists in Neurodegenerative Diseases

Current Medicinal Chemistry, Jul 1, 2022

Background: Alzheimer’s disease (AD) is the most common form of dementia worldwide, with approxim... more 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 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. Method: 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.

Pyrazolo [4,3-E]1,2,4-triazolo[1,5-c]pyrimidine derivates a new class of potent and selective human A3 adenosine receptor antagonists

Drug Development Research, 2000

ABSTRACT

An Open Question: Is the A2A Adenosine Receptor a Novel Target for Alzheimer’s Disease Treatment?

Frontiers in Pharmacology, Mar 22, 2021

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

International Journal of Molecular Sciences, May 2, 2022

The A 2A adenosine receptor, a member of the P1 purinergic receptor family, plays a crucial role ... more The A 2A 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-β 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-1β and IL-18 release through caspase-1 activation. NLRP3 inhibition provides neuroprotection, and in recent years adenosine, through the A 2A 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 A 2A 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

International Journal of Molecular Sciences, Jan 22, 2022

Adenosine exerts an important role in the modulation of central nervous system (CNS) activity. Th... more 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 A 1 and A 2A 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.

Targeting A3 and A2A adenosine receptors in the fight against cancer

Expert Opinion on Therapeutic Targets, Jun 12, 2019

-Adenosine is an endogenous and ubiquitous nucleoside, deriving from dephosphorylation of both in... more -Adenosine is an endogenous and ubiquitous nucleoside, deriving from dephosphorylation of both intracellular and extracellular ATP, rising under stressed conditions present in several pathologies and acting through interaction with four GPCR receptors, named A1, A2A, A2B and A3. -Adenosine plays a crucial role in the regulation of cancer cell biology by regulating both tumor and immune cells, through interaction with its cognate A3 and A2A receptors, respectively. Specifically, a vicious cycle of tumor hypoxia, increased adenosine concentrations, immune suppression and cancer growth implies the use of adenosine receptor ligands in tumors. -Highly selective A3 agonists with potential as anticancer drugs have been developed, exploiting their anti-proliferative and proapoptotic effects. These ligands represent a new and original anticancer approach, addressing for the first time both cancer and healthy immune cells. -A3 receptors are overexpressed in almost all cancer types, indicating that A3 agonists could offer the opportunity of an innovative personalized cancer therapy. The A3 receptor represents an effective tumor biomarker, being its overexpression at baseline in correlation with a positive response in patients. -Potent and selective A2A receptor antagonists have been developed based on the awareness that hypoxic generation of adenosine in tumors is crucial for their immuno-escape A2A receptorsmediated. Based on the ability of these compounds to activate the immune system, clinical trials have been designed to evaluate their antitumor efficacy in combination with immunological drugs. -The A3 agonist Namodenoson, as well as A2A antagonists Preladenant, PBF-509, CPI-444 and AZD4635, in clinical development, demonstrate a good safety profile, no side effects, and an acceptable pharmacokinetic behavior, thereby giving hope for the future for a new generation of drugs capable of changing the fate of numerous types of tumor.

Design, Synthesis, and Pharmacological Characterization of 2-(2-Furanyl)thiazolo[5,4-<i>d</i>]pyrimidine-5,7-diamine Derivatives: New Highly Potent A<sub>2A</sub> Adenosine Receptor Inverse Agonists with Antinociceptive Activity

Journal of Medicinal Chemistry, Nov 29, 2016

In this study, we describe the design and synthesis of new N 5 -substituted-2-(2-furanyl) thiazol... more In this study, we describe the design and synthesis of new N 5 -substituted-2-(2-furanyl) thiazolo [5,4-d]pyrimidine-5,7-diamines (2-18) and their pharmacological characterization as A2A adenosine receptor (AR) antagonists by using in vitro and in vivo assays. In competition binding experiments two derivatives (13 and 14) emerged as outstanding ligands showing two different affinity values (KH and KL) for the hA2A receptor with the high affinity KH value in the femtomolar range. The in vitro functional activity assays, performed by using cyclic AMP experiments, assessed that they behave as potent inverse agonists at the hA2A AR. Compounds 13 and 14 were evaluated for their antinociceptive activity in acute experimental models of pain showing an effect equal to or greater than that of morphine. Overall, these novel inverse agonists might represent potential drug candidates for an alternative approach to the management of pain.

Synthesis and biological evaluation of a new series of 2-amino-3-aroyl thiophene derivatives as agonist allosteric modulators of the A 1 adenosine receptor. A position-dependent effect study

European journal of medicinal chemistry, Aug 1, 2015

The 2-amino-3-(p-chlorobenzoyl)thiophene scaffold has been widely employed as a pharmacophore for... more The 2-amino-3-(p-chlorobenzoyl)thiophene scaffold has been widely employed as a pharmacophore for the identification of small molecules acting as allosteric modulators at the adenosine A 1 receptor. A new series of 2-amino-3-(p-chlorobenzoyl)-4-benzyl-5-arylthiophene derivatives, characterized by the absence as well as the presence of electron-releasing or electronwithdrawing groups on the phenyl ring at the 4-and 5-positions of the thiophene ring, were identified as positive allosteric enhancers at the adenosine A 1 receptor in binding (saturation, competition and dissociation kinetics) and functional assays. To better understand the positional requirements of substituents on the 2-amino-3-(p-chlorobenzoyl)thiophene core, the corresponding regioisomeric 4-aryl-5-benzylthiophene analogues were synthesized and found to possess reduced allosteric enhancer activity.

Adenosine Receptors and Cancer

Handbook of experimental pharmacology, 2009

The A 1 , A 2A , A 2B and A 3 G-protein-coupled cell surface adenosine receptors (ARs) are found ... more The A 1 , A 2A , A 2B and A 3 G-protein-coupled cell surface adenosine receptors (ARs) are found to be upregulated in various tumor cells. Activation of the receptors by specific ligands, agonists or antagonists, modulates tumor growth via a range of signaling pathways. The A 1 AR was found to play a role in preventing the development of glioblastomas. This antitumor effect of the A 1 AR is mediated via tumor-associated microglial cells. Activation of the A 2A AR results in inhibition of the immune response to tumors via suppression of T regulatory cell function and inhibition of natural killer cell cytotoxicity and tumor-specific CD4+/CD8+ activity. Therefore, it is suggested that pharmacological inhibition by specific antagonists may enhance immunotherapeutics in cancer therapy. Activation of the A 2B AR plays a role in the development of tumors via upregulation of the expression levels of angiogenic factors in microvascular endothelial cells. In contrast, it was evident that activation of A 2B AR results in inhibition of ERK1/2 phosphorylation and MAP kinase activity, which are involved in tumor cell growth signals. Finally, A 3 AR was found to be highly expressed in tumor cells and tissues while low expression levels were noted in normal cells or adjacent tissue. Receptor expression in the tumor tissues was directly correlated to disease severity. The high receptor expression in the tumors was attributed to overexpression of NF-κB, known to act as an A 3 AR transcription factor. Interestingly, high A 3 AR expression levels were found in peripheral blood mononuclear cells (PBMCs) derived from tumor-bearing animals and cancer patients, reflecting receptor status in the tumors. A 3 AR agonists were found to induce tumor growth inhibition, both in vitro and in vivo, via modulation of the Wnt and the NF-κB signaling pathways. Taken together, A 3 ARs that are abundantly expressed in tumor cells may be targeted by specific A 3 AR agonists, leading to tumor growth inhibition. The unique characteristics of these A 3 AR agonists make them attractive as drug candidates.

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

Molecules, Apr 21, 2022

The A 2A adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. ... more The A 2A 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-β extracellular accumulation and tau hyperphosphorylation, causing neuronal cell death, cognitive deficit, and memory loss. Interestingly, in vitro and in vivo studies have demonstrated that A 2A 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 A 2A adenosine receptors in AD animal and human studies and reports the state of the art of A 2A 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 A 2A 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.

Pharmacological characterization ofalpha2-adrenoceptors in human cerebral cortex and platelets

Deregulation of Adenosine Receptors in Psoriatic Epidermis: An Option for Therapeutic Treatment

Journal of Investigative Dermatology, 2017

Comparative molecular field analysis (CoMFA) of a series of selective adenosine receptor A2A antagonists

Drug Development Research, Feb 1, 1999

ABSTRACT

Preparation of sulfonamido nucleosides as human adenosine A3 receptro agonists and antitumor agents

The invention realizes that a series of sulfonamido derivs. I, wherein wherein Ar is an aryl grou... more The invention realizes that a series of sulfonamido derivs. I, wherein wherein Ar is an aryl group; and R and R1 are independently H, alkyl, aryl, heteroaryl, alkenyl, cycloalkenyl, cycloalkyl, alkoxy, alkynyl, and where taken together R and R1 may form a or carbocyclic or heterocyclic fused ring system which includes both alicyclic and arom. structures with a conserved uronamide group at the 5' position provide superior A3 receptor affinity as well as selectivity. These new adenosine agonists are sulfonamido derivs. N-substituted with aliph. groups (cyclic or linear) or arom. radicals. Mediation of the A3 receptor has been found to induce behavioral depression and protect against cerebral ischemia, and to induce apoptosis in HL-60 human leukemia cells. The A3 adenosine receptor is known to mediate many processes, such as inflammation, hypotension, and mast cell deregulation. These compds. can be used to treat cancer. This particularly includes cancers that express elevated levels of A3 receptors. This would include, but not be limited to, ovarian cancer, breast cancer, colon cancer, and melanoma. Thus, nucleoside II was prepd. and tested in vitro as adenosine A3 receptor agonist and antitumor agent

M3 muscarinic receptors in peripheral lung parenchima of patients with chronic obstructive pulmonary disease

Adenosine in a Human Model of Hypoxic Foam Cells

Foam cells formation by oxidized low-density lipoprotein (oxLDL) accumulation in macrophages is c... more Foam cells formation by oxidized low-density lipoprotein (oxLDL) accumulation in macrophages is crucial for development of atherosclerosis. Macrophage foam cell formation is an important process in atherosclerotic plaque development.1 Atherosclerosis is initiated by dysfunction of endothelial cells at lesion-prone sites in the walls of arteries, which results in monocyte infiltration into the arterial intima. These cells differentiated into macrophages, which then internalize large amounts of oxidized low-density lipoprotein forming cholesterol-laden macrophages called “foam cells”, which in turn give rise to fatty streaks in the arterial wall. As the atherosclerotic lesion develops, the arterial wall tickness increases and oxygen diffusion into the intima is markedly reduced.2 These hypoxic regions contain large number of foam cells revealing that these cells experience hypoxia during the development of atherosclerotic lesions. Hypoxia has been demonstrated in atherosclerosis and hypoxia-inducible factor-1 (HIF-1) has been shown to promote intraplaque angiogenesis and foam cells development. Adenosine is a proangiogenic purine nucleoside released from ischemic and hypoxic tissues. In this study we found that Adenosine, under hypoxia, stimulates HIF-1α accumulation by activating adenosine receptors. This study provides the first evidence that adenosine antagonists may be useful to block important steps in the atherosclerotic plaque development ado-induced. (1) Lusis, AJ. Atherosclerosis. Nature. 2000, 407, 233-241. (2) Björnheden, T.; Levin, M.; Evaldsson, M.; Wiklund, O. Evidence of hypoxic areas within the arterial wall in vivo. Arterioscler. Thromb. Vasc. Biol. 1999, 19, 870-876

Effect of chronic caffeine intake on A2A adenosine receptors in human neutrophils

Pharmacological characterization of purine receptors in bovine fibroblast-like synoviocytes

Growing evidence also suggests that extracellular nucleotides, acting through purinergic receptor... more Growing evidence also suggests that extracellular nucleotides, acting through purinergic receptors, play a central role in the regulation of bone and cartilage metabolism. Fibroblast-like synoviocytes are closely involved in the pathogenesis of joint destruction by an increased proliferation and by the secretion of a wide range of pro-inflammatory mediators including cytokines, growth factors and lipid mediators. The aim of the present study was to investigate from a biochemical, physico chemical and functional point of view A1, A2A, A2B and A3 adenosine receptors and P2X1 and P2X3 purinergic receptors in bovine fibroblast-like synoviocytes. Saturation binding experiments on purine receptors in bovine fibroblast-like synoviocytes were performed and demonstrated the presence of all the adenosine receptors and P2X1 and P2X3 purinergic subtypes. The affinity of typical adenosine and purinergic ligands were studied through competition binding experiments. Thermodynamic analysis of the binding of purine receptors was studied to investigate the forces driving drug-receptor coupling and to verify if adenosine and purinergic ligands were thermodynamically discriminated. The potency of typical purine agonists and antagonists was evaluated in different functional assays such as intracellular cyclic AMP accumulation, PGE2 release and NO production. In particular, A2A but not A3 agonists were involved in the negative modulation of PGE2 synthesis confirming the anti-inflammatory role of the A2A receptors. Well-known purinergic agonists were able to increase NO and PGE2 production suggesting that the stimulation of purinergic receptors increase the inflammation processes

Adenosine A2A receptors of human circulating blood elements

Drug Development Research, Nov 1, 1998

ABSTRACT

Adenosinergic System Involvement in Ischemic Stroke Patients’ Lymphocytes

Cells, Apr 25, 2020

Adenosine modulates many physiological processes through the interaction with adenosine receptors... more Adenosine modulates many physiological processes through the interaction with adenosine receptors (ARs) named as A 1 , A 2A , A 2B, and A 3 ARs. During ischemic stroke, adenosine mediates neuroprotective and anti-inflammatory effects through ARs activation. One of the dominant pathways generating extracellular adenosine involves the dephosphorylation of ATP by ecto-nucleotidases CD39 and CD73, which efficiently hydrolyze extracellular ATP to adenosine. The aim of the study is to assess the presence of ARs in lymphocytes from ischemic stroke patients compared to healthy subjects and to analyze changes in CD39 and CD73 expression in CD4 + and CD8 + lymphocytes. Saturation binding experiments revealed that A 2A ARs affinity and density were significantly increased in ischemic stroke patients whilst no differences were found in A 1 , A 2B, and A 3 ARs. These results were also confirmed in reverse transcription (RT)-polymerase chain reaction (PCR) assays where A 2A AR mRNA levels of ischemic stroke patients were higher than in control subjects. In flow cytometry experiments, the percentage of CD73 + cells was significantly decreased in lymphocytes and in T-lymphocyte subclasses CD4 + and CD8 + obtained from ischemic stroke patients in comparison with healthy individuals. These data corroborate the importance of the adenosinergic system in ischemic stroke and could open the way to more targeted therapeutic approaches and biomarker development for ischemic stroke.

A2A Adenosine Receptor Antagonists in Neurodegenerative Diseases

Current Medicinal Chemistry, Jul 1, 2022

Background: Alzheimer’s disease (AD) is the most common form of dementia worldwide, with approxim... more 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 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. Method: 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.