Pharmacological characterisation and inhibitory effects of (2R,3R,4S,5R)-2-(6-amino-2-{[(1S)-2-hydroxy-1-(phenylmethyl)ethyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3,4-furandiol, a novel ligand that demonstrates both adenosine A2A receptor agonist and adenosine A3 receptor antagonist activity

Bevan, Nicola; Butchers, P.R.; Cousins, Rick; Coates, Jill; Edgar, Emma V.; Morrison, Val; Sheehan, Michael J.; Reeves, J.J.; Wilson, David J.

doi:10.1016/j.ejphar.2007.01.094

Cited by 28 publications

(27 citation statements)

References 38 publications

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“…11 The findings that truncated nucleosides 4g and 4m serve as dual ligands acting at the hA 2A and hA 3 ARs are similar to the pharmacological profile of a more heavily 2,5′-substituted adenosine derivative, which was also a hA 2A AR agonist and hA 3 AR antagonist. 20 …”

Section: Resultsmentioning

confidence: 99%

Structure–Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A_2A and A₃ Adenosine Receptor Ligands

Hou¹,

Majik²,

Kim³

et al. 2011

J. Med. Chem.

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Truncated N6-substituted-4′-oxo- and 4′-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A2A and A3 adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA2AAR, but hydrophobic C8 substitution abolished binding at the hA2AAR. However, most of synthesized compounds displayed medium to high binding affinity at the hA3AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA2AAR agonists. C2 substitution probed geometrically through hA2AAR-docking, was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA2AAR agonist and hA3AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

Structure–Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A_2A and A₃ Adenosine Receptor Ligands

Hou¹,

Majik²,

Kim³

et al. 2011

J. Med. Chem.

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“…One could speculate that the use of A 2A R agonists during chronic inflammatory conditions might selectively inhibit proinflammatory cytokine production of activated microglia, whereas the addition of A 3 R antagonists might potentiate inhibitory effects of adenosine on unstimulated microglia as well. The recent description of a synthetic compound that demonstrates both adenosine A 2A R agonist and A 3 R antagonist activity therefore holds pharmacological promise (49). However, the widespread expression of adenosine receptors on different cells and tissues and the described neuroprotective effects of A 2A R antagonists in animal models for stroke and Parkinson's disease (50, 51) warrant caution when extrapolating these results to therapeutic applications.…”

Section: Discussionmentioning

confidence: 97%

Differential Expression of Adenosine A3 Receptors Controls Adenosine A2A Receptor-Mediated Inhibition of TLR Responses in Microglia

Putten¹,

Zuiderwijk‐Sick²,

Straalen³

et al. 2009

The Journal of Immunology

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Microglia activation is a prominent feature in many neuroinflammatory disorders. Unrestrained activation can generate a chronic inflammatory environment that might lead to neurodegeneration and autoimmunity. Extracellular adenosine modulates cellular activation through adenosine receptor (ADORA)-mediated signaling. There are four ADORA subtypes that can either increase (A2A and A2B receptors) or decrease (A1 and A3 receptors) intracellular cyclic AMP levels. The expression pattern of the subtypes thus orchestrates the cellular response to extracellular adenosine. We have investigated the expression of ADORA subtypes in unstimulated and TLR-activated primary rhesus monkey microglia. Activation induced an up-regulation of A2A and a down-regulation of A3 receptor (A3R) levels. The altered ADORA-expression pattern sensitized microglia to A2A receptor (A2AR)-mediated inhibition of subsequent TLR-induced cytokine responses. By using combinations of subtype-specific agonists and antagonists, we revealed that in unstimulated microglia, A2AR-mediated inhibitory signaling was effectively counteracted by A3R-mediated signaling. In activated microglia, the decrease in A3R-mediated signaling sensitized them to A2AR-mediated inhibitory signaling. We report a differential, activation state-specific expression of ADORA in microglia and uncover a role for A3R as dynamically regulated suppressors of A2AR-mediated inhibition of TLR-induced responses. This would suggest exploration of combinations of A2AR agonists and A3R antagonists to dampen microglial activation during chronic neuroinflammatory conditions.

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“…mRNA for the adenosine A 3 receptor is highest in the central nervous system, liver, and lung [19,20]. A recent study showed that a ligand which combines adenosine A 2A receptor agonist and A 3 receptor antagonist activity inhibits the release of preformed granule proteins from neutrophils [21]. Another recent study showed that the A 3 R on neutrophils is additionally involved in neutrophilic chemotaxis [22].…”

Section: Discussionmentioning

confidence: 99%

Adenosine receptors in COPD and asymptomatic smokers: effects of smoking cessation

et al. 2009

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Our group has shown that 1-year smoking cessation persisted or increased airway inflammation in chronic obstructive pulmonary disease (COPD). We compared adenosine and adenosine receptor (AR) expression in COPD and asymptomatic smokers (AS) before and after 1-year smoking cessation. Sputum cytospins and bronchial biopsies of (ex)smoking COPD patients and AS were studied for A(1)R, A(2A)R, A(2B)R, and A(3)R expression. Adenosine and inflammatory mediators were measured in sputum supernatants. At baseline, COPD patients had lower levels of adenosine and higher levels of vascular endothelial growth factor in sputum than AS. Smoking cessation induced significantly different effects in COPD than in AS, i.e. an increase in percentages of A(3)R expressing neutrophils and A(1)R expressing macrophages in COPD as increase in adenosine and monocyte chemoattractant protein-1 levels in sputum. Adenosine-related effector mechanisms may contribute to the persistence and progression of airway inflammation in COPD following 1-year smoking cessation.

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Cited by 28 publications

References 38 publications

Structure–Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A_2A and A₃ Adenosine Receptor Ligands

Structure–Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A_2A and A₃ Adenosine Receptor Ligands

Differential Expression of Adenosine A3 Receptors Controls Adenosine A2A Receptor-Mediated Inhibition of TLR Responses in Microglia

Adenosine receptors in COPD and asymptomatic smokers: effects of smoking cessation

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Cited by 28 publications

References 38 publications

Structure–Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A2A and A3 Adenosine Receptor Ligands

Structure–Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A2A and A3 Adenosine Receptor Ligands

Differential Expression of Adenosine A3 Receptors Controls Adenosine A2A Receptor-Mediated Inhibition of TLR Responses in Microglia

Adenosine receptors in COPD and asymptomatic smokers: effects of smoking cessation

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Product

Resources

About

Structure–Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A_2A and A₃ Adenosine Receptor Ligands

Structure–Activity Relationships of Truncated C2- or C8-Substituted Adenosine Derivatives as Dual Acting A_2A and A₃ Adenosine Receptor Ligands