Pharmacological characterization of novel A3 adenosine receptor-selective antagonists

Park, Kyung Sun; Jiang, Jinling; Kim, Yong-Chul; Olah, Mark E.; Stiles, Gary L.; Ji, Xingchen

doi:10.1016/s0028-3908(97)00104-4

Cited by 141 publications

(127 citation statements)

References 33 publications

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“…At the human A 3 receptor, effective and selective antagonists have been reported Jacobson et al, 1997]. Such antagonists might be suitable for therapeutic needs; however, antagonists selective in the rat are still needed as research tools.…”

Section: Discussionmentioning

confidence: 99%

“…An adenosine derivative substituted at N 6 -and 5′-positions, N 6 -(3-iodobenzyl)-5′-N-methylcarboxamidoadenosine (IB-MECA) [GalloRodriguez et al, 1994], is 50-fold more selective for rat brain A 3 receptors in binding experiments and is also selective in in vivo behavioral experiments. Even more highly selective A 3 agonists, such as Cl-IB-MECA (Compound 1a), have been developed [Jacobson, 1998], but only recently were selective antagonists for A 3 receptors reported Kim et al, 1996;Jacobson et al, 1997]. A selective A 3 antagonist might prove to be anti-inflammatory [Ali et al, 1990;Walker et al, 1997] or cerebroprotective , based on inference from studies with agonists.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activation and desensitization of rat A3-adenosine receptors by selective adenosine derivatives and xanthine-7-ribosides

Park¹,

Hoffmann²,

Kim³

et al. 1998

Drug Dev. Res.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activation and desensitization of rat A3-adenosine receptors by selective adenosine derivatives and xanthine-7-ribosides

Park¹,

Hoffmann²,

Kim³

et al. 1998

Drug Dev. Res.

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“…In addition, we also monitored the phosphorylation states of Akt1-3, GSK-3a/b, RSK-1 and 2, and MSK2. Altogether, these signaling arrays included 18 kinases, which have been implicated as major regulators of mast cell function (19). Fig.…”

Section: Assessment Of the Gi3-mediated Signaling Networkmentioning

confidence: 99%

Activation of Mast Cells by Trimeric G Protein Gi3; Coupling to the A3 Adenosine Receptor Directly and upon T Cell Contact

Baram

Dekel

Mekori

et al. 2010

The Journal of Immunology

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Mast cells are key players in mediating and amplifying allergic and inflammatory reactions. Previously, we identified the G-protein, Gi3, as the cellular target of receptor mimetic basic secretagogues that activate mast cell independently of IgE. In this study, we demonstrate that Gi3 is the cellular target of the adenosine A3 receptor (A3R), a G-protein coupled receptor involved in inflammation and the pathophysiology of asthma. By using a cell permeable peptide comprising the C-terminal end of Gαi3 fused to an importation sequence (ALL1) as a selective inhibitor of Gi3 signaling, we show that by coupling to Gi3, the A3R stimulates multiple signaling pathways in human mast cells, leading to upregulation of cytokines, chemokines, and growth factors. We further show that after contact with activated T cell membranes, endogenous adenosine binds to and activates the A3R, resulting in Gi3-mediated signaling. Specifically, the majority of ERK1/2 signaling initiated by contact with activated T cell membranes, is mediated by Gi3, giving rise to ALL1-inhibitable cellular responses. These results unveil the physiological G-protein coupled receptor that couples to Gi3 and establish the important role played by this G-protein in inflammatory conditions that involve adenosine-activated mast cells.

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“…28,29 Binding of [ 35 S]GTP-γ-S was studied in membranes prepared from CHO (Chinese hamster ovary) cells stably expressing human A 1 or A 3 receptors ( Table 2). The nonselective adenosine agonist NECA (5′-N-ethyluronamidoadenosine) caused a concentration-dependent increase in the level of the guanine nucleotide bound (Figure 2A).…”

Section: Biological Activitymentioning

confidence: 99%

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

et al. 2000

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Adenosine receptor agonists have cardioprotective, cerebroprotective, and antiinflammatory properties. We report that a carbocyclic modification of the ribose moiety incorporating ring constraints is a general approach for the design of A 1 and A 3 receptor agonists having favorable pharmacodynamic properties. While simple carbocyclic substitution of adenosine agonists greatly diminishes potency, methanocarba-adenosine analogues have now defined the role of sugar puckering in stabilizing the active adenosine receptor-bound conformation and thereby have allowed identification of a favored isomer. In such analogues a fused cyclopropane moiety constrains the pseudosugar ring of the nucleoside to either a Northern (N) or Southern (S) conformation, as defined in the pseudorotational cycle. In binding assays at A 1 , A 2A , and A 3 receptors, (N)-methanocarba-adenosine was of higher affinity than the (S)-analogue, particularly at the human A 3 receptor (N/S affinity ratio of 150). (N)-Methanocarba analogues of various N 6 -substituted adenosine derivatives, including cyclopentyl and 3-iodobenzyl, in which the parent compounds are potent agonists at either A 1 or A 3 receptors, respectively, were synthesized. The N 6 -cyclopentyl derivatives were A 1 receptor-selective and maintained high efficacy at recombinant human but not rat brain A 1 receptors, as indicated by stimulation of binding of [ 35 S]GTP-γ-S. The (N)-methanocarba-N 6 -(3-iodobenzyl)adenosine and its 2-chloro derivative had K i values of 4.1 and 2.2 nM at A 3 receptors, respectively, and were highly selective partial agonists. Partial agonism combined with high functional potency at A 3 receptors (EC 50 < 1 nM) may produce tissue selectivity. In conclusion, as for P2Y 1 receptors, at least three adenosine receptors favor the ribose (N)-conformation.In work designed to develop potent and selective agents, the structure-activity relationships of adenosine derivatives as ligands (principally agonists) at the four subtypes of adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) have been explored extensively. Adenosine receptor agonists 1,2 are being studied for their potential use as antiarrhythmic, 3 antinociceptive, 4 and antilipolytic 5,6 agents (A 1 subtype); as cerebroprotective 7 and cardioprotective 8 agents (A 1 and A 3 subtypes); and as hypotensive 9 and antipsychotic 10 agents (A 2A subtype).* Address correspondence to Dr. Kenneth A. Jacobson, Chief, Molecular Recognition Section, Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC, Bethesda, MD 20892-0810. Tel: (301) In general, for adenosine agonists, numerous modifications of the N 6 -position with cycloalkyl and other hydrophobic moieties provide selectivity for A 1 receptors, although the affinities of these N 6 -substituted adenosine derivatives (e.g. N 6 -cyclopentyl) at A 3 receptors are often intermediate between their respective A 1 and A 2A affinities. 1 Structurally, few ribose modifications, other than amide substitution at the 5′-position, are tolerated in adenosine agonists. An intact f...

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Pharmacological characterization of novel A3 adenosine receptor-selective antagonists

Cited by 141 publications

References 33 publications

Activation and desensitization of rat A3-adenosine receptors by selective adenosine derivatives and xanthine-7-ribosides

Activation and desensitization of rat A3-adenosine receptors by selective adenosine derivatives and xanthine-7-ribosides

Activation of Mast Cells by Trimeric G Protein Gi3; Coupling to the A3 Adenosine Receptor Directly and upon T Cell Contact

Methanocarba Analogues of Purine Nucleosides as Potent and Selective Adenosine Receptor Agonists

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