Current Understanding of the Role of Adenosine Receptors in Cancer.

Cancer, a complex array of diseases, involves the unbridled proliferation and dissemination of aberrant cells in the body, forming tumors that can infiltrate neighboring tissues and metastasize to distant sites. With over 200 types, each cancer has unique attributes, risks, and treatment avenues. Therapeutic options encompass surgery, chemotherapy, radiation therapy, hormone therapy, immunotherapy, targeted therapy, or a blend of these methods.

Dual Anta-Inhibitors Targeting Protein Kinase CK1δ and A Adenosine Receptor Useful in Neurodegenerative Disorders.

Currently, the number of patients with neurodegenerative pathologies is estimated at over one million, with consequences also on the economic level. Several factors contribute to their development, including overexpression of A adenosine receptors (AAR) in microglial cells and up-regulation and post-translational alterations of some casein kinases (CK), among them, CK-1δ. The aim of the work was to study the activity of AAR and CK1δ in neurodegeneration using in-house synthesized A/CK1δ dual anta-inhibitors and to evaluate their intestinal absorption.

"Dual Anta-Inhibitors" of the A Adenosine Receptor and Casein Kinase CK1delta: Synthesis, Biological Evaluation, and Molecular Modeling Studies.

Based on a screening of a chemical library of A adenosine receptor (AR) antagonists, a series of di- and tri-substituted adenine derivatives were synthesized and tested for their ability to inhibit the activity of the enzyme casein kinase 1 delta (CK1δ) and to bind adenosine receptors (ARs). Some derivatives, here called "dual anta-inhibitors", demonstrated good CK1δ inhibitory activity combined with a high binding affinity, especially for the AAR. The -methyl-(2-benzimidazolyl)-2-dimethyamino-9-cyclopentyladenine (, IC = 0.

The possible role of the nucleoside adenosine in countering skin aging: A review.

Skin aging is a complex biological process. Skin aspect is considered as a sign of well-being and of beauty. In view of this, noninvasive and/or minimally invasive anti-aging strategies were developed.

A Adenosine Receptor Antagonists: Are Triazolotriazine and Purine Scaffolds Interchangeable?

The A adenosine receptor (AAR) is one of the four subtypes activated by nucleoside adenosine, and the molecules able to selectively counteract its action are attractive tools for neurodegenerative disorders. In order to find novel AAR ligands, two series of compounds based on purine and triazolotriazine scaffolds were synthesized and tested at ARs. Compound was also tested in an in vitro model of neuroinflammation.

A patent review of adenosine A receptor antagonists (2016-present).

Introduction: A adenosine receptor (AAR) plays a crucial role in pathophysiologic conditions associated with high adenosine release, typical of airway inflammatory pathologies, gastrointestinal disorders, cancer, asthma, type 2 diabetes, and atherosclerosis. In some pathologies, simultaneous inactivation of A and AARs is desirable to have a synergism of action that leads to a greater efficacy of the pharmacological treatment and less side effects due to the dose of drug administered. In this context, it is strongly required to identify molecules capable of selectively antagonizing AAR or A/AARs.

A Adenosine Receptor Antagonists with Nucleoside Structures and Their Anticancer Activity.

The overexpression of the A adenosine receptor (AR) in a number of cancer cell types makes it an attractive target for tumor diagnosis and therapy. Hence, in the search for new AAR ligands, a series of novel 2,-disubstituted adenosines (Ados) was synthesized and tested in radioligand binding and functional assays at ARs. Derivatives bearing a 2-phenethylamino group in the -position were found to exert higher AAR affinity and selectivity than the corresponding -(2,2-diphenylethyl) analogues.

Design and Synthesis of Novel Thiazolo[5,4-d]pyrimidine Derivatives with High Affinity for Both the Adenosine A and A Receptors, and Efficacy in Animal Models of Depression.

New compounds with a 7-amino-2-arylmethyl-thiazolo[5,4-d]pyrimidine structure were synthesized and evaluated in vitro for their affinity and/or potency at the human (h) A, hA, hA, and hA adenosine receptors (ARs). Several compounds (, -, , , ) were characterized by nanomolar and subnanomolar binding affinities for the hA and the hA AR, respectively. Results of molecular docking studies supported the in vitro results.

Combined Therapy of AAR Agonists and AAR Antagonists in Neuroinflammation.

Alzheimer's, Parkinson's, and multiple sclerosis are neurodegenerative diseases related by neuronal degeneration and death in specific areas of the central nervous system. These pathologies are associated with neuroinflammation, which is involved in disease progression, and halting this process represents a potential therapeutic strategy. Evidence suggests that microglia function is regulated by A and A adenosine receptors (AR), which are considered as neuroprotective and neurodegenerative receptors, respectively.

Efficacy of acetylcholinesterase inhibitors in Alzheimer's disease.

Alzheimer's disease (AD), the most common cause of adult-onset dementia is characterized by a progressive decline of cognitive functions accompanied by behavioral manifestations. The main class of drugs currently used for the treatment of AD are acetylcholinesterase/cholinesterase inhibitors (ChE-Is). The first ChE-I licensed for symptomatic treatment of AD was tacrine.

Acetylshikonin isolated from Lithospermum erythrorhizon roots inhibits dihydrofolate reductase and hampers autochthonous mammary carcinogenesis in Δ16HER2 transgenic mice.

Breast cancer (BC) is the most common cancer in women and, among different BC subtypes, triple negative (TN) and human epidermal growth factor receptor 2 (HER2)-positive BCs have the worst prognosis. In this study, we investigated the anticancer activity of the root ethanolic and hexane extracts from Lithospermum erythrorhizon, a traditional Chinese herbal medicine known also as tzu ts'ao or tzu-ken, against in vitro and in vivo models of TNBC and HER2-positive BC. Treatment with L.

Adenosine Receptors as Neuroinflammation Modulators: Role of A Agonists and A Antagonists.

The pathological condition of neuroinflammation is caused by the activation of the neuroimmune cells astrocytes and microglia. The autacoid adenosine seems to be an important neuromodulator in this condition. Its main receptors involved in the neuroinflammation modulation are AAR and AAR.

Discovery of first-in-class multi-target adenosine A receptor antagonists-carbonic anhydrase IX and XII inhibitors. 8-Amino-6-aryl-2-phenyl-1,2,4-triazolo [4,3-a]pyrazin-3-one derivatives as new potential antitumor agents.

This paper describes identification of the first-in-class multi-target adenosine A receptor antagonists-carbonic anhydrase (CA) IX and XII inhibitors, as new potential antitumor agents. To obtain the multi-acting ligands, the 8-amino-2,6-diphenyltriazolo[4,3-a]pyrazin-3-one, a potent adenosine hA receptor (AR) antagonist, was taken as lead compound. To address activity against the tumor-associated CA isoforms, it was modified by introduction of different substituents (OH, COOH, CONHOH, SONH) on the 6-phenyl ring or on a phenyl pendant connected to the former through different spacers.

New 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives. Evaluation of different moieties on the 6-aryl ring to obtain potent and selective human A adenosine receptor antagonists.

In this work, further structural investigations on the 8-amino-2-phenyl-6-aryl-1,2,4-triazolo[4,3-a]pyrazin-3-one series were carried out to achieve potent and selective human A adenosine receptor (AR) antagonists. Different ether and amide moieties were attached at the para-position of the 6-phenyl ring, thus leading to compounds 1-9 and 10-18, respectively. Most of these moieties contained terminal basic rings (pyrrolidine, morpholine, piperidine and substituted piperazines) which were thought to confer good physicochemical and drug-like properties.

Outstanding insecticidal activity and sublethal effects of Carlina acaulis root essential oil on the housefly, Musca domestica, with insights on its toxicity on human cells.

Carlina acaulis (Compositae) is traditionally used for food and medicinal purposes in central and southern Europe. Its root essential oil (EO), mainly composed by carlina oxide, is included in the BELFRIT botanical list of food supplements. It is also recognized as a potent mosquito larvicide.

Structure-Based Optimization of Coumarin hA Adenosine Receptor Antagonists.

Adenosine receptors participate in many physiological functions. Molecules that may selectively interact with one of the receptors are favorable multifunctional chemical entities to treat or decelerate the evolution of different diseases. 3-Arylcoumarins have already been studied as neuroprotective agents by our group.

Update on novel purinergic P2X3 and P2X2/3 receptor antagonists and their potential therapeutic applications.

: Purinergic P2X3-P2X2/3 receptors are placed in nociceptive neurons' strategic location and show unique desensitization properties; hence, they represent an attractive target for many pain-related diseases. Therefore, a broad interest from academic and pharmaceutical scientists has focused on the search for P2X3 and P2X2/3 receptor ligands and has led to the discovery of numerous new selective antagonists. Some of them have been studied in clinical trials for the treatment of pathological conditions such as bladder disorders, gastrointestinal and chronic obstructive pulmonary diseases.

Non-Nucleoside Agonists of the Adenosine Receptors: An Overview.

Potent and selective adenosine receptor (AR) agonists are of pharmacological interest for the treatment of a wide range of diseases and conditions. Among these derivatives, nucleoside-based agonists represent the great majority of molecules developed and reported to date. However, the limited availability of compounds selective for a specific AR subtype (i.

Antioxidant-Conjugated 1,2,4-Triazolo[4,3-]pyrazin-3-one Derivatives: Highly Potent and Selective Human A Adenosine Receptor Antagonists Possessing Protective Efficacy in Neuropathic Pain.

New 8-amino-6-aryl-1,2,4-triazolo[4,3-]pyrazin-3-ones were designed to obtain dual antioxidant-human A adenosine receptor (hA AR) antagonists. Two sets of compounds were synthesized, the first featuring phenol rings at the 6-position, the second bearing the lipoyl and 4-hydroxy-3,5-di-but-benzoyl residues appended by different linkers on the 6-phenyl ring. Several new triazolopyrazines () were potent and selective hA AR antagonists ( = 0.

New A adenosine receptor antagonists: a structure-based upside-down interaction in the receptor cavity.

Adenosine receptor antagonists are generally based on heterocyclic core structures presenting substituents of various volumes and chemical-physical profiles. Adenine and purine-based adenosine receptor antagonists have been reported in literature. In this work we combined various substituents in the 2, 6, and 8-positions of 9-ethylpurine to depict a structure-affinity relationship analysis at the human adenosine receptors.

New sensible method to quantize the intestinal absorption of receptor ligands.

In recent years, special attention has been paid to the A adenosine receptor (AAR) as a possible pharmacological target to treat intestinal inflammation. In this work, it was set up a novel method to quantify the concentration of a promising anti-inflammatory agent inside and outside of intestinal barrier using the everted gut sac technique. The compound chosen for the present study is one of the most potent and selective AAR agonist reported so far, named AR 170 (N-methyl-2-phenylethynyl-5'-N-methylcarboxamidoadenosine).

Investigation on 2',3'--Substituted ATP Derivatives and Analogs as Novel P2X3 Receptor Antagonists.

Antagonists of the purinergic P2X3 receptors represent promising drugs for the treatment of inflammation and pain. The ATP derivative 2',3'--(2,4,6-trinitrophenyl)-ATP (TNP-ATP) has been described as a potent competitive inhibitor of this receptor. In this work, the design and synthesis of novel TNP-ATP analogues bearing alkyl groups in the 2',3'-position are reported.

Novel 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives as potent human adenosine A and A receptor antagonists. Evaluation of their protective effect against β-amyloid-induced neurotoxicity in SH-SY5Y cells.

In this work, an enlarged series of 1,2,4-triazolo[4,3-a]pyrazin-3-ones was designed to target the human (h) A adenosine receptor (AR) or both hA and hA ARs. The novel 8-amino-1,2,4-triazolopyrazin-3-one derivatives 1-25 featured a phenyl or a benzyl pendant at position 2 while different aryl/heteroaryl substituents were placed at position 6. Two compounds (8 and 10) endowed with high affinity (K = 7.