Use of knockout mice to explore CNS effects of adenosine

Lopes, Cátia R.; Lourenço, Vanessa S.; Tomé, Ângelo R.; Cunha, Rodrigo A.; Canas, Paula M.

doi:10.1016/j.bcp.2020.114367

Cited by 15 publications

(6 citation statements)

References 192 publications

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“…Finally, ZINC19943625, ZINC13555217, and ZINC04698406 were screened to activate A1. They may reduce pain by regulating cGMP-PKG signaling pathway and reducing the activity of adenylate cyclase [ 42 ]. The supply of A2aR-ZINC19370372, A2aR-ZINC20176051, and A2aR-ZINC57263068 can reduce the production of the intracellular second messenger cAMP and inactivate the cAMP/PKA/CREB signaling pathway, resulting in degradation of the pain.…”

Section: Discussionmentioning

confidence: 99%

In silico identification of A1 agonists and A2a inhibitors in pain based on molecular docking strategies and dynamics simulations

Zhang

Zheng

et al. 2021

Purinergic Signalling

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Most recently, the adenosine is considered as one of the most promising targets for treating pain, with few side effects. It exists in the central nervous system, and plays a key role in nociceptive afferent pathway. It is reported that the A1 receptor (A1R) could inhibit Ca2+ channels to reduce the pain like analgesic mechanism of morphine. And, A2a receptor (A2aR) was reported to enhance the accumulation of AMP (cAMP) and released peptides from sensory neurons, resulting in constitutive activation of pain. Much evidence showed that A1R and A2aR could be served as the interesting targets for the treatment of pain. Herein, virtual screening was utilized to identify the small molecule compounds towards A1R and A2aR, and top six molecules were considered as candidates via amber scores. The molecular dynamic (MD) simulations and molecular mechanics/generalized born surface area (MM/GBSA) were employed to further analyze the affinity and binding stability of the six molecules towards A1R and A2aR. Moreover, energy decomposition analysis showed significant residues in A1R and A2aR, including His1383, Phe1276, and Glu1277. It provided basics for discovery of novel agonists and antagonists. Finally, the agonists of A1R (ZINC19943625, ZINC13555217, and ZINC04698406) and inhibitors of A2aR (ZINC19370372, ZINC20176051, and ZINC57263068) were successfully recognized. Taken together, our discovered small molecules may serve as the promising candidate agents for future pain research.

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Section: Discussionmentioning

confidence: 99%

In silico identification of A1 agonists and A2a inhibitors in pain based on molecular docking strategies and dynamics simulations

Zhang

Zheng

et al. 2021

Purinergic Signalling

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“…This point should be earnestly considered in developing drugs that target the A 3 AR. The application of various genetically modified small animal models, including global [ 28 ] and conditional mouse A 3 AR gene knockout (KO) models [ 29 ], is necessary to implicate the A 3 AR in specific human diseases and to validate effectiveness and specificity of potential clinical leads. The difference in A 3 AR antagonist pharmacology between human and mouse led to the introduction of an “A 3 AR functionally humanized” mouse model in which a human/mouse chimera that maintains faithful coupling to phosphoinositol 3-kinase (PI3K) Υ-signaling in mast cells replaced the mouse A 3 AR [ 30 ].…”

Section: Species Differences Among Adenosine Receptorsmentioning

confidence: 99%

Species dependence of A3 adenosine receptor pharmacology and function

Gao

Auchampach

Jacobson

2022

Purinergic Signalling

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Efforts to fully understand pharmacological differences between G protein-coupled receptor (GPCR) species homologues are generally not pursued in detail during the drug development process. To date, many GPCRs that have been successfully targeted are relatively well-conserved across species in amino acid sequence and display minimal variability of biological effects. However, the A 3 adenosine receptor (AR), an exciting drug target for a multitude of diseases associated with tissue injury, ischemia, and inflammation, displays as little as 70% sequence identity among mammalian species (e.g., rodent vs. primate) commonly used in drug development. Consequently, the pharmacological properties of synthetic A 3 AR ligands vary widely, not only in binding affinity, selectivity, and signaling efficacy, but to the extent that some function as agonists in some species and antagonists in others. Numerous heterocyclic antagonists that have nM affinity at the human A 3 AR are inactive or weakly active at the rat and mouse A 3 ARs. Positive allosteric modulators, including the imidazo [4,5-c]quinolin-4-amine derivative LUF6000, are only active at human and some larger animal species that have been evaluated (rabbit and dog), but not rodents. A 3 AR agonists evoke systemic degranulation of rodent, but not human mast cells. The rat A 3 AR undergoes desensitization faster than the human A 3 AR, but the human homologue can be completely re-sensitized and recycled back to the cell surface. Thus, comprehensive pharmacological evaluation and awareness of potential A 3 AR species differences are critical in studies to further understand the basic biological functions of this unique AR subtype. Recombinant A 3 ARs from eight different species have been pharmacologically characterized thus far. In this review, we describe in detail current knowledge of species differences in genetic identity, G protein-coupling, receptor regulation, and both orthosteric and allosteric A 3 AR pharmacology.

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“…Their expression on astrocytes regulates glutamate uptake and Na + /K + ATPase, contributing to the role of A 2A Rs as selective mediators of synaptic plasticity [ 78 ]. Increasing the complexity of adenosine’s neuromodulatory action [ 79 , 80 ], adenosine receptors can also form heterodimers with other G-protein coupled receptors [ 81 ]. Activation of antagonistic A 2A -D 2 receptor heteromers, first identified in striatal membrane preparations [ 82 ] and found in GABAergic striatopallidal neurons [ 83 ], results in reduced D 2 receptor affinity for agonists.…”

Section: The Adenosine System: Purinergic Receptorsmentioning

confidence: 99%

Adenosine, Schizophrenia and Cancer: Does the Purinergic System Offer a Pathway to Treatment?

Hamoud

Bach

Kakrecha

et al. 2022

IJMS

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For over a century, a complex relationship between schizophrenia diagnosis and development of many cancers has been observed. Findings from epidemiological studies are mixed, with reports of increased, reduced, or no difference in cancer incidence in schizophrenia patients. However, as risk factors for cancer, including elevated smoking rates and substance abuse, are commonly associated with this patient population, it is surprising that cancer incidence is not higher. Various factors may account for the proposed reduction in cancer incidence rates including pathophysiological changes associated with disease. Perturbations of the adenosine system are hypothesized to contribute to the neurobiology of schizophrenia. Conversely, hyperfunction of the adenosine system is found in the tumor microenvironment in cancer and targeting the adenosine system therapeutically is a promising area of research in this disease. We outline the current biochemical and pharmacological evidence for hypofunction of the adenosine system in schizophrenia, and the role of increased adenosine metabolism in the tumor microenvironment. In the context of the relatively limited literature on this patient population, we discuss whether hypofunction of this system in schizophrenia, may counteract the immunosuppressive role of adenosine in the tumor microenvironment. We also highlight the importance of studies examining the adenosine system in this subset of patients for the potential insight they may offer into these complex disorders.

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Use of knockout mice to explore CNS effects of adenosine

Cited by 15 publications

References 192 publications

In silico identification of A1 agonists and A2a inhibitors in pain based on molecular docking strategies and dynamics simulations

In silico identification of A1 agonists and A2a inhibitors in pain based on molecular docking strategies and dynamics simulations

Species dependence of A3 adenosine receptor pharmacology and function

Adenosine, Schizophrenia and Cancer: Does the Purinergic System Offer a Pathway to Treatment?

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