Adenosine and Purinergic Receptors: Regulation and Essential Role in Human Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: 31 October 2024 | Viewed by 846

Special Issue Editors


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Guest Editor
Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy
Interests: molecular modeling; drug design; purinergic receptors

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Guest Editor
Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy
Interests: synthesis of heterocycles; structure–activity relationship; adenosine receptors

E-Mail Website
Guest Editor
Molecular Modeling Section (MMS), Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy
Interests: molecular modeling; drug design; purinergic receptors

Special Issue Information

Dear Colleagues,

The purinergic signaling system comprises both adenosine receptors (ARs) and purinergic receptors (P2Rs), where adenosine and nucleotides act as extracellular messengers, respectively.

In particular, adenosine exerts its function through the activation of four AR subtypes, A1, A2A, A2B, and A3, which are G protein-coupled receptors, while P2Rs comprise both ionotropic receptors (P2X1-7R) and metabotropic receptors (P2Y1,2,4,6,11-14R). The signaling pathways activated by ligand–receptor interaction are cross-linked with other transmitter networks to regulate numerous key physiological processes like proliferation, differentiation, and apoptosis. Thus, the deregulation of the system establishes pathological conditions that include, but are not limited to, inflammation, cancer, and neurodegeneration. Few adenosinergic and purinergic drugs have been approved to date. Great efforts are still focused on the research and development of ligands, with emerging interest in the field of allosteric modulation, biased agonism, and bitopic ligands. On the other hand, even more efforts are ongoing in understanding the pathophysiological implications of the different receptors in order to validate them as targets in specific diseases.

With this Special Issue, we aim to shed light on the pharmacology of AR and P2R, as well as present the advancements in the development of ligands towards them. We look forward to receiving your contributions.

Dr. Veronica Salmaso
Dr. Stephanie Federico
Prof. Dr. Stefano Moro
Guest Editors

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Keywords

  • adenosine receptors
  • adenosine
  • purinergic signaling
  • P2 receptors
  • GPCRs
  • neurodegeneration
  • cancer
  • pain
  • inflammation
  • ischemia

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Published Papers (1 paper)

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14 pages, 1664 KiB  
Article
Functionalized Congeners of 2H-Chromene P2Y6 Receptor Antagonists
by Paola Oliva, Asmita Pramanik, Young-Hwan Jung, Sarah A. Lewicki, Jamie M. Mwendwa, Jong Hwan Park and Kenneth A. Jacobson
Cells 2024, 13(16), 1366; https://doi.org/10.3390/cells13161366 - 16 Aug 2024
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Abstract
The P2Y6 receptor (P2Y6R), a Gq-coupled receptor, is a potential drug discovery target for various inflammatory and degenerative conditions. Antagonists have been shown to attenuate colitis, acute lung injury, etc. In the search for competitive antagonists, we have [...] Read more.
The P2Y6 receptor (P2Y6R), a Gq-coupled receptor, is a potential drug discovery target for various inflammatory and degenerative conditions. Antagonists have been shown to attenuate colitis, acute lung injury, etc. In the search for competitive antagonists, we have investigated the SAR of 3-nitro-2-(trifluoromethyl)-2H-chromene derivatives, although high affinity is lacking. We now reveal that long-chain amino-functionalized congeners display greatly enhanced affinity in the antagonism of UDP-induced Ca2+ mobilization in human (h) P2Y6R-transfected 1321N1 astrocytoma cells. A 6-(Boc-amino-n-heptylethynyl) analogue 30 (MRS4940) had an IC50 of 162 nM, which was a 123-fold greater affinity than the corresponding unprotected primary alkylamine, 107-fold greater than the corresponding pivaloyl derivative 30, and 132-fold selective compared to the P2Y14R. However, similar Boc-amino chains attached at the 8-position produced weak µM affinity. Thus, the P2Y6R affinity depended on the chain length, attachment point, and terminal functionality. Off-target activities, at 45 sites, were tested for acylamino derivatives 20, 24, 26, 30, 31, and 37, which showed multiple interactions, particularly at the biogenic amine receptors. The more potent analogues may be suitable for evaluation in inflammation and cancer models, which will be performed in future studies. Full article
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