Cloned adenosine A3 receptors: Pharmacological properties, species differences and receptor functions

doi:10.1016/0165-6147(94)90011-6

Trends in Pharmacological Sciences

Volume 15, Issue 8, August 1994, Pages 298-306

https://doi.org/10.1016/0165-6147(94)90011-6 Get rights and content

Abstract

In this review, Joel Linden summarizes what is known about a new and intriguing member of the adenosine receptor family, the A₃ receptor. This receptor exhibits unusually large differences in structure, tissue distribution and pharmacological properties between species. Rat A₃ receptors are resistant to blockade by xanthine antagonists, but human and sheep A₃ receptors can be potently blocked by certain xanthines, notably acidic 8-phenylxanthines. One function of the receptor is to facilitate degradation of mast cells, and a role for mast cells and A₃ receptors in mediating myocardial preconditioning has been proposed. Therefore, selective antagonists of A₃ receptors have potential for the treatment of allergic, inflammatory and possibly ischaemic disorders.

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A₃ adenosine receptor (A₃AR) agonists are effective at limiting injury caused by ischemia/reperfusion injury of the heart in experimental animal models. However, understanding of their mechanism of action, which is likely multifactorial, remains incomplete. In prior studies, it has been demonstrated that A₃AR-mediated ischemic protection is blocked by glibenclamide and is absent in Kir6.2 gene ablated mice that lack the pore-forming subunit of the ATP-sensitive potassium (K_ATP) channel, suggesting one contributing mechanism may involve accelerated activation of K_ATP channels. However, presence of A₃ARs in the myocardium has yet to be established. Utilizing a whole-cell recording technique, in this study we confirm functional expression of the A₃AR in adult mouse ventricular cardiomyocytes, coupled to activation of ATP-dependent potassium (K_ATP) channels via G_i inhibitory proteins. We further show that ischemic protection provided by the selective A₃AR agonist CP-532,903 in an isolated, buffer-perfused heart model is lost completely in Adora3^{LoxP/LoxP;Myh6-Cre} mice, which is a newly developed model developed and comprehensively described herein whereby the A₃AR gene (Adora3) is deleted exclusively in cardiomyocytes. Our findings, taken together with previously published work, are consistent with the hypothesis that A₃AR agonists provide ischemic tolerance, at least in part, by facilitating opening of myocardial K_ATP channels.
Enantiomeric 4-Acylamino-6-alkyloxy-2 Alkylthiopyrimidines As Potential A<inf>3</inf>Adenosine Receptor Antagonists: HPLC Chiral Resolution and Absolute Configuration Assignment by a Full Set of Chiroptical Spectroscopy
2016, Chirality
The chiral separation of enantiomeric couples of three potential A₃ adenosine receptor antagonists: (R/S)‐N‐(6‐(1‐phenylethoxy)‐2‐(propylthio)pyrimidin‐4‐yl)acetamide (1), (R/S)‐N‐(2‐(1‐phenylethylthio)‐6‐propoxypyrimidin‐4‐yl)acetamide (2), and (R/S)‐N‐(2‐(benzylthio)‐6‐sec‐butoxypyrimidin‐4‐yl)acetamide (3) was achieved by high‐performance liquid chromatography (HPLC). Three types of chiroptical spectroscopies, namely, optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD), were applied to enantiomeric compounds. Through comparison with Density Functional Theory (DFT) calculations, encompassing extensive conformational analysis, full assignment of the absolute configuration (AC) for the three sets of compounds was obtained. Chirality 28:434–440, 2016. © 2016 Wiley Periodicals, Inc.
1,2,4-Triazolo[1,5-a]quinoxaline derivatives and their simplified analogues as adenosine A<inf>3</inf> receptor antagonists. Synthesis, structure-affinity relationships and molecular modeling studies
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The 1,2,4-triazolo[1,5-a]quinoxaline (TQX) scaffold was extensively investigated in our previously reported studies and recently, our attention was focused at position 5 of the tricyclic nucleus where different acyl and carboxylate moieties were introduced (compounds 2–15). This study produced some interesting compounds endowed with good hA₃ receptor affinity and selectivity. In addition, to find new insights about the structural requirements for hA₃ receptor–ligand interaction, the tricyclic TQX ring was destroyed yielding some 1,2,4-triazole derivatives (compounds 16–23). These simplified compounds, though maintaining the crucial structural requirements for adenosine receptor–ligand interaction, have a very low hA₃ adenosine receptor affinity, the only exception being compound 23 (1-[3-(4-methoxyphenyl)-1-phenyl-1H-1,2,4-triazol-5-yl]-3-phenylurea) endowed with a K_i value in the micro-molar range and high hA₃ selectivity versus both hA₁ and hA_2A AR subtypes. Evaluation of the side products obtained in the herein reported synthetic pathways led to the identification of some new triazolo[1,5-a]quinoxalines as hA₃AR antagonists (compounds 24–27). These derivatives, though lacking the classical structural requirements for the anchoring at the hA₃ receptor site, show high hA₃ affinity and in some case selectivity versus hA₁ and hA_2A subtypes. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA₃ receptor.
Adenosine and its receptors as therapeutic targets: An overview
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Selective and potent adenosine A<inf>3</inf> receptor antagonists by methoxyaryl substitution on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold
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The influence of diverse methoxyphenyl substitution patterns on the N-(2,6-diarylpyrimidin-4-yl)acetamide scaffold is herein explored in order to modulate the A₃ adenosine receptor antagonistic profile. As a result, novel ligands exhibiting excellent potency (K_i on A₃ AR < 20 nM) and selectivity profiles (above 100-fold within the adenosine receptors family) are reported. Moreover, our joint theoretical and experimental approach allows the identification of novel pharmacophoric elements conferring A₃AR selectivity, first established by a robust computational model and thereafter characterizing the most salient features of the structure–activity and structure–selectivity relationships in this series.
P2Y<inf>11</inf> purinoceptor mediates the ATP-enhanced chemotactic response of rat neutrophils
2012, Journal of Pharmacological Sciences
ATP and hydrolysis products of ATP like adenosine regulate the chemotaxis of neutrophils by activating purinoceptors and adenosine receptors. The present study was designed to examine exogenous ATP, activation of purinoceptors, and activation of A₃ adenosine receptor as key steps in the signal cascades that control cell orientation and migration of rat neutrophils. One or more of those steps might be potential therapeutic targets for treatment of inflammatory diseases. The chemotaxis of rat neutrophils was stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP) and measured with an EZ-TAXIScan apparatus. The effects of apyrase, exogenous ATP, suramin (P2X and P2Y blocker), PPADS (a P2X blocker), TNP-ATP (P2X₁ and P2X₃ antagonist), and Reactive Blue 2 (a P2Y blocker) on the chemotactic response were also investigated. Rat neutrophil chemotaxis was significantly suppressed by apyrase. fMLP induced rat neutrophil chemotaxis was potentiated by ATP, blocked by suramin, not affected by PPADS or TNP-ATP, and significantly inhibited by RB-2. Western blotting showed that A₃, P2Y₂, and P2Y₁₁ were expressed in rat neutrophils. The chemotactic response of rat neutrophils to fMLP stimulation is potentiated by ATP via P2Y₁₁ purinoceptors but not P2X purinoceptors or A₃ adenosine receptor, and that the response plays a critical role in host defense and pathogenicity.
[Supplementary Movies: available only at http://dx.doi.org/10.1254/jphs.12173FP]

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Trends in Pharmacological Sciences

ReviewsCloned adenosine A3 receptors: Pharmacological properties, species differences and receptor functions

Abstract

FEBS Lett.

Biochem. Biophys. Acta Mol. Cell Res.

J. Allergy Clin. Immunol.

J. Biol. Chem.

FEBS Lett.

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Prog. Neurobiol.

Trends Pharmacol. Sci.

Trends Pharmacol Sci.

FEBS Lett.

FEBS Lett.

FEBS Lett.

Cardiovasc. Res.

Eur. J. Biochem.

Reviews
Cloned adenosine A₃ receptors: Pharmacological properties, species differences and receptor functions