scholarly journals Uncovering the Mechanisms of Adenosine Receptor-Mediated Pain Control: Focus on the A3 Receptor Subtype

2021 ◽  
Vol 22 (15) ◽  
pp. 7952
Author(s):  
Elisabetta Coppi ◽  
Federica Cherchi ◽  
Elena Lucarini ◽  
Carla Ghelardini ◽  
Felicita Pedata ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adenosine Receptor ◽  
Pain Control ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Opioid Analgesics ◽  
Receptor Subtype ◽  
A3ar Agonist ◽  
A3 Adenosine Receptor ◽  
Gi Protein

Agonists of the Gi protein-coupled A3 adenosine receptor (A3AR) have shown important pain-relieving properties in preclinical settings of several pain models. Active as a monotherapy against chronic pain, A3AR agonists can also be used in combination with classic opioid analgesics. Their safe pharmacological profile, as shown by clinical trials for other pathologies, i.e., rheumatoid arthritis, psoriasis and fatty liver diseases, confers a realistic translational potential, thus encouraging research studies on the molecular mechanisms underpinning their antinociceptive actions. A number of pathways, involving central and peripheral mechanisms, have been proposed. Recent evidence showed that the prototypical A3AR agonist Cl-IB-MECA and the new, highly selective, A3AR agonist MRS5980 inhibit neuronal (N-type) voltage-dependent Ca2+ currents in dorsal root ganglia, a known pain-related mechanism. Other proposed pathways involve reduced cytokine production, immune cell-mediated responses, as well as reduced microglia and astrocyte activation in the spinal cord. The aim of this review is to summarize up-to-date information on A3AR in the context of pain, including cellular and molecular mechanisms underlying this effect. Based on their safety profile shown in clinical trials for other pathologies, A3AR agonists are proposed as novel, promising non-narcotic agents for pain control.

Navigating in chromone chemical space: discovery of novel and distinct A3 adenosine receptor ligands

RSC Advances ◽  
2015 ◽  
Vol 5 (96) ◽  
pp. 78572-78585 ◽  
Author(s):  
F. Cagide ◽  
A. Gaspar ◽  
J. Reis ◽  
D. Chavarria ◽  
S. Vilar ◽  
...  
Keyword(s):  
Adenosine Receptor ◽  
Chemical Space ◽  
Receptor Subtype ◽  
Receptor Ligands ◽  
Specific Receptor ◽  
A3 Adenosine Receptor ◽  
Adenosine Receptor Ligands ◽  
Effective Drugs

One of the major hurdles in the development of effective drugs targeting GPCRs is finding ligands selective for a specific receptor subtype. Here we describe a potent and selective hormone-based hA3 AR ligand (Ki of 167 nM) with a remarkable selectivity.

scholarly journals Immunostimulatory Properties of Chemotherapy in Breast Cancer: From Immunogenic Modulation Mechanisms to Clinical Practice

2022 ◽  
Vol 12 ◽  
Author(s):  
Jinguo Zhang ◽  
Shuaikang Pan ◽  
Chen Jian ◽  
Li Hao ◽  
Jie Dong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Suppressor Cells ◽  
Treg Cells ◽  
Immune Effector ◽  
Chemotherapy Drugs ◽  
Cytotoxic Treatment

Breast cancer (BC) is the most common malignancy among females. Chemotherapy drugs remain the cornerstone of treatment of BC and undergo significant shifts over the past 100 years. The advent of immunotherapy presents promising opportunities and constitutes a significant complementary to existing therapeutic strategies for BC. Chemotherapy as a cytotoxic treatment that targets proliferation malignant cells has recently been shown as an effective immune-stimulus in multiple ways. Chemotherapeutic drugs can cause the release of damage-associated molecular patterns (DAMPs) from dying tumor cells, which result in long-lasting antitumor immunity by the key process of immunogenic cell death (ICD). Furthermore, Off-target effects of chemotherapy on immune cell subsets mainly involve activation of immune effector cells including natural killer (NK) cells, dendritic cells (DCs), and cytotoxic T cells, and depletion of immunosuppressive cells including Treg cells, M2 macrophages and myeloid-derived suppressor cells (MDSCs). Current mini-review summarized recent large clinical trials regarding the combination of chemotherapy and immunotherapy in BC and addressed the molecular mechanisms of immunostimulatory properties of chemotherapy in BC. The purpose of our work was to explore the immune-stimulating effects of chemotherapy at the molecular level based on the evidence from clinical trials, which might be a rationale for combinations of chemotherapy and immunotherapy in BC.

scholarly journals Free-Energy Calculations for Bioisosteric Modifications of A3 Adenosine Receptor Antagonists

2019 ◽  
Vol 20 (14) ◽  
pp. 3499
Author(s):  
Zuzana Jandova ◽  
Willem Jespers ◽  
Eddy Sotelo ◽  
Hugo Gutiérrez-de-Terán ◽  
Chris Oostenbrink
Keyword(s):  
Free Energy ◽  
Adenosine Receptor ◽  
Drug Targets ◽  
Free Energy Calculations ◽  
Receptor Subtype ◽  
Energy Calculations ◽  
Meta Position ◽  
A3 Adenosine Receptor ◽  
Dynamics Simulations ◽  
The Impact

Adenosine receptors are a family of G protein-coupled receptors with increased attention as drug targets on different indications. We investigate the thermodynamics of ligand binding to the A3 adenosine receptor subtype, focusing on a recently reported series of diarylacetamidopyridine inhibitors via molecular dynamics simulations. With a combined approach of thermodynamic integration and one-step perturbation, we characterize the impact of the charge distribution in a central heteroaromatic ring on the binding affinity prediction. Standard charge distributions according to the GROMOS force field yield values in good agreement with the experimental data and previous free energy calculations. Subsequently, we examine the thermodynamics of inhibitor binding in terms of the energetic and entropic contributions. The highest entropy penalties are found for inhibitors with methoxy substituents in meta position of the aryl groups. This bulky group restricts rotation of aromatic rings attached to the pyrimidine core which leads to two distinct poses of the ligand. Our predictions support the previously proposed binding pose for the o-methoxy ligand, yielding in this case a very good correlation with the experimentally measured affinities with deviations below 4 kJ/mol.

scholarly journals [1,2,4]Triazolo[1,5-c]pyrimidines as adenosine receptor antagonists: Modifications at the 8 position to reach selectivity towards A3 adenosine receptor subtype

2018 ◽  
Vol 157 ◽  
pp. 837-851 ◽  
Author(s):  
Stephanie Federico ◽  
Enrico Margiotta ◽  
Veronica Salmaso ◽  
Giorgia Pastorin ◽  
Sonja Kachler ◽  
...  
Keyword(s):  
Adenosine Receptor ◽  
Receptor Subtype ◽  
Receptor Antagonists ◽  
A3 Adenosine Receptor

New Trends in Anti-Cancer Therapy: Combining Conventional Chemotherapeutics with Novel Immunomodulators

2018 ◽  
Vol 25 (36) ◽  
pp. 4758-4784 ◽  
Author(s):  
Amy L. Wilson ◽  
Magdalena Plebanski ◽  
Andrew N. Stephens
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
Immune System ◽  
Cancer Therapy ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Tumour Microenvironment ◽  
Immune Checkpoints ◽  
Tumour Regression ◽  
Cell Trafficking

Cancer is one of the leading causes of death worldwide, and current research has focused on the discovery of novel approaches to effectively treat this disease. Recently, a considerable number of clinical trials have demonstrated the success of immunomodulatory therapies for the treatment of cancer. Monoclonal antibodies can target components of the immune system to either i) agonise co-stimulatory molecules, such as CD137, OX40 and CD40; or ii) inhibit immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its corresponding ligand PD-L1. Although tumour regression is the outcome for some patients following immunotherapy, many patients still do not respond. Furthermore, chemotherapy has been the standard of care for most cancers, but the immunomodulatory capacity of these drugs has only recently been uncovered. The ability of chemotherapy to modulate the immune system through a variety of mechanisms, including immunogenic cell death (ICD), increased antigen presentation and depletion of regulatory immune cells, highlights the potential for synergism between conventional chemotherapy and novel immunotherapy. In addition, recent pre-clinical trials indicate dipeptidyl peptidase (DPP) enzyme inhibition, an enzyme that can regulate immune cell trafficking to the tumour microenvironment, as a novel cancer therapy. The present review focuses on the current immunological approaches for the treatment of cancer, and summarizes clinical trials in the field of immunotherapy as a single treatment and in combination with chemotherapy.

Recent Advances on QSAR-Based Profiling of Agonist and Antagonist A3 Adenosine Receptor Ligands

2013 ◽  
Vol 13 (9) ◽  
pp. 1048-1068 ◽  
Author(s):  
Changliang Deng ◽  
Feng Luan ◽  
Maykel Cruz- Monteagudo ◽  
Fernanda Borges ◽  
M. Natalia D. S. Cordeiro
Keyword(s):  
Adenosine Receptor ◽  
Receptor Ligands ◽  
Recent Advances ◽  
A3 Adenosine Receptor ◽  
Agonist And Antagonist ◽  
Adenosine Receptor Ligands

Potential Therapeutic Targets of Curcumin, Most Abundant Active Compound of Turmeric Spice: Role in the Management of Various Types of Cancer

2020 ◽  
Vol 15 ◽  
Author(s):  
Saleh A. Almatroodi ◽  
Mansoor Ali Syed ◽  
Arshad Husain Rahmani
Keyword(s):  
Clinical Trials ◽  
Cancer Cells ◽  
Active Compound ◽  
Molecular Mechanisms ◽  
Human Subjects ◽  
Cell Signalling ◽  
Chemopreventive Agents ◽  
Signalling Molecules ◽  
Cancer Management ◽  
Induced Apoptosis

Background:: Curcumin, an active compound of turmeric spice is one of the most-studies natural compounds and have been widely recognized as chemopreventive agents. Several molecular mechanisms have been proven, curcumin and its analogs play a role in cancer prevention through modulating various cell signaling pathways as well as inhibition of carcinogenesis process. Objective:: To study the potential role of curcumin in the management of various types of cancer through modulating cell signalling molecules based on available literature and recent patents. Methods:: A wide-ranging literature survey was performed based on Scopus, PubMed, PubMed central and Google scholar for the implication of curcumin in cancer management along with special emphasis on human clinical trials. Moreover, patents were searched through www.google.com/patents, www.freepatentsonline.com and www.freshpatents.com. Result:: Recent studies based on cancer cells have proven that curcumin have potential effects against cancer cells, prevent the growth of cancer and act as cancer therapeutic agents. Besides, curcumin exerted anticancer effects through inducing apoptosis, activating tumor suppressor genes, cell cycle arrest, inhibiting tumor angiogenesis, initiation, promotion and progression stages of tumor. It was established that co-treatment of curcumin and anti-cancer drugs could induce apoptosis and also play a significant role in the suppression of the invasion and metastasis of cancer cells. Conclusion:: Accumulating evidences suggest that curcumin has potentiality to inhibit cancer growth, induced apoptosis and modulate various cell signalling pathways molecules. Well-designed clinical trials of curcumin based on human subjects are still needed to establish the bioavailability, mechanism of action, efficacy and safe dose in the management of various cancers.

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