Allosteric Modulation of Adenosine A2A Receptors as a New Therapeutic Avenue

Korkutata, Mustafa; Agrawal, Lokesh; Lazarus, Michael

doi:10.3390/ijms23042101

Cited by 17 publications

(14 citation statements)

References 127 publications

(168 reference statements)

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“…To provide therapeutic benefit, allosteric modulators can be considered based on three properties that were outlined by Korkutata et al (129) 1. affinity modulation of the binding of the orthosteric ligand to the receptor; 2. modulation of the receptor decoding signaling triggered by the orthosteric ligand; 3. possible effects of the allosteric modulator on the receptor conformation and/or membrane location in the absence of the orthosteric ligand.…”

Section: A Novel Pharmacological Approach Based On Targeting Alloster...mentioning

confidence: 99%

Modulating brain integrative actions as a new perspective on pharmacological approaches to neuropsychiatric diseases

et al. 2023

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A critical aspect of drug development in the therapy of neuropsychiatric diseases is the “Target Problem”, that is, the selection of a proper target after not simply the etiopathological classification but rather the detection of the supposed structural and/or functional alterations in the brain networks. There are novel ways of approaching the development of drugs capable of overcoming or at least reducing the deficits without triggering deleterious side effects. For this purpose, a model of brain network organization is needed, and the main aspects of its integrative actions must also be established. Thus, to this aim we here propose an updated model of the brain as a hyper-network in which i) the penta-partite synapses are suggested as key nodes of the brain hyper-network and ii) interacting cell surface receptors appear as both decoders of signals arriving to the network and targets of central nervous system diseases. The integrative actions of the brain networks follow the “Russian Doll organization” including the micro (i.e., synaptic) and nano (i.e., molecular) levels. In this scenario, integrative actions result primarily from protein-protein interactions. Importantly, the macromolecular complexes arising from these interactions often have novel structural binding sites of allosteric nature. Taking G protein-coupled receptors (GPCRs) as potential targets, GPCRs heteromers offer a way to increase the selectivity of pharmacological treatments if proper allosteric drugs are designed. This assumption is founded on the possible selectivity of allosteric interventions on G protein-coupled receptors especially when organized as “Receptor Mosaics” at penta-partite synapse level.

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Section: A Novel Pharmacological Approach Based On Targeting Alloster...mentioning

confidence: 99%

Modulating brain integrative actions as a new perspective on pharmacological approaches to neuropsychiatric diseases

et al. 2023

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“…However, some clinical trials of A 2A R were discontinued due to their side effects, short half‐life of compounds, low brain penetration, or a lack of effects 31 . In order to avoid adverse effects, scientists have made many efforts to discover allosteric modulators of A 2A R, which can selectively exert a physiologic response only where and when the orthosteric ligand is released 32 . Although A 2A R has contradictory roles in different cells or tissues, allosteric modulators of A 2A R can target specific sites.…”

Section: Modulation Of A2armentioning

confidence: 99%

“…31 In order to avoid adverse effects, scientists have made many efforts to discover allosteric modulators of A 2A R, which can selectively exert a physiologic response only where and when the orthosteric ligand is released. 32 Although A 2A R has contradictory roles in different cells or tissues, allosteric modulators of A 2A R can target specific sites. For example, it was proved A 2A R agonists strongly induced sleep, however, due to their adverse effects, including hypotension and tachycardia, which precluded their use in insomnia.…”

Section: Modulation Of a 2 A Rmentioning

confidence: 99%

Pathophysiology roles for adenosine 2A receptor in obesity and related diseases

Cai

Chen

et al. 2022

Obesity Reviews

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Obesity, a burgeoning worldwide health system challenge, is associated with several comorbidities, including non-alcoholic fatty liver disease (NAFLD), diabetes, atherosclerosis, and osteoarthritis, leading to serious problems to people's health. Adenosine is a critical extracellular signaling molecule that has essential functions in regulating most organ systems by binding to four G-protein-coupled adenosine receptors, denoted A 1 , A 2A , A 2B , and A 3 . Among the receptors, a growing body evidence highlights the key roles of the adenosine 2A receptor (A 2A R) in obesity and related diseases. In the current review, we summarize the effects of A 2A R in obesity and obesity-associated non-alcoholic fatty liver disease, diabetes, atherosclerosis, and osteoarthritis, to clarify the complicated impacts of A 2A R on obesity and related diseases.

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“…Meanwhile, adenosine 2A receptors (A2ARs), as one of four different types of adenosine receptors, have emerged as attractive targets for therapeutic intervention for neurodegenerative disorders [15][16][17]. A2ARs are expressed at high levels in several brain cell types and control various CNS functions, including locomotion, anxiety, depression, inhibition of excitatory neuronal activity and sleep regulation [18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Early postnatal activation of A2ARs alleviates social deficits by attenuating the abnormal infiltration of peripheral neutrophils in the BTBR T + Itpr3 tf /J mouse model of autism

Zhou

Yang

et al. 2022

Preprint

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Background Previous studies have mainly focused on the immediate effect of drugs on autism spectrum disorders (ASDs) and complex heterogeneous neurodevelopmental disorders that have been proven to be involved with the chronic inflammation of the central nervous system. Our prior work has explored the positive role of activation of adenosine 2A receptors (A2ARs) in protecting adult BTBR T+ Itpr3tf/J mice against autism-related behaviour from the early postnatal period. However, the exact mechanism underlying the protection of A2ARs has not been comprehensively investigated. Methods The persistent protection of early postnatal activation of A2ARs in adult BTBR mice was detected utilizing behaviour tests. Pathological variation in the peripheral blood of autism patients was analysed by transcriptomic analysis, including MROAST and protein–protein interaction (PPI) analysis. The clues were further explored and validated by real-time (RT) PCR, western blotting, immunohistochemistry and transcriptomic analysis in the mouse cortex. The blood brain barrier of mice was identified by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results Abnormal activation of myeloid cells, especially neutrophils, was detected in the peripheral blood of autism patients and the BTBR mouse cortex. The BBB permeability of BTBR mice was significantly increased, which may have facilitated the abnormal infiltration of neutrophils observed in the BTBR mouse cortex. Furthermore, the early postnatal activation of A2ARs effectively reverses the abnormal activation and invasion of neutrophils in the mouse cortex and might result in the significant moderation of autism-related behaviour in adult BTBR mice, followed by a decrease in chronic inflammation in the mouse cortex during the early postnatal period. Conclusions We found abnormal myeloid cells in autism patients and BTBR mice and increased infiltration of neutrophils in the mouse cortex. We concluded that the early activation of A2ARs could effectively decrease the autism-related behaviour of adult BTBR mice by reversing the abnormal activation of myeloid cells and the pathological invasion of neutrophils in the mouse cortex.

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Allosteric Modulation of Adenosine A2A Receptors as a New Therapeutic Avenue

Cited by 17 publications

References 127 publications

Modulating brain integrative actions as a new perspective on pharmacological approaches to neuropsychiatric diseases

Modulating brain integrative actions as a new perspective on pharmacological approaches to neuropsychiatric diseases

Pathophysiology roles for adenosine 2A receptor in obesity and related diseases

Early postnatal activation of A2ARs alleviates social deficits by attenuating the abnormal infiltration of peripheral neutrophils in the BTBR T + Itpr3 tf /J mouse model of autism

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