A3-adenosine receptors: Design of selective ligands and therapeutic prospects

Ka, Jacobson; Ho, Kim; Sm, Siddiqi; Me, Olah; Gl, Stiles; Dk, von Lubitz

doi:10.1358/dof.1995.020.07.531583

Cited by 122 publications

(154 citation statements)

References 35 publications

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“…Relaxant responses to CGS 21680 were only observed at concentrations greater than 10 mM and as the a nity of CGS 21680 at A 2A receptors is 15 nM (Jacobson et al, 1995), these relaxant responses are unlikely to be mediated via A 2A receptors. This was con®rmed by use of 50 mM 8-SPT, which failed to block the responses to CGS 21680.…”

Section: Controlmentioning

confidence: 93%

“…Recently a third receptor termed the A 3 receptor has been cloned (Zhou et al, 1992) which is activated by adenosine and some analogues such as N 6 -(3-iodo-benzyl)-adenosine-5'-Nmethyluronamide (IB-MECA, K i =1.1 nM, Jacobson et al, 1995). Unlike A 1 and A 2 receptors, the rat A 3 receptor is resistant to blockade by all but a few methylxanthines, one of which is 1,3-dipropyl -8-(4-acrylate)phenylxanthine (BWA1433, K i =15 mM, Jacobson et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

“…Unlike A 1 and A 2 receptors, the rat A 3 receptor is resistant to blockade by all but a few methylxanthines, one of which is 1,3-dipropyl -8-(4-acrylate)phenylxanthine (BWA1433, K i =15 mM, Jacobson et al, 1995). Because the under®ned site in the aorta shares some characteristics in common with the A 3 receptor we investigated the activity of these A 3 receptor ligands in the present study.…”

Section: Introductionmentioning

confidence: 99%

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Activation of two sites by adenosine receptor agonists to cause relaxation in rat isolated mesenteric artery

Prentice

Payne

Hourani

1997

British J Pharmacology

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1 In this study we have characterized the receptor(s) in the rat mesenteric artery mediating relaxant responses to adenosine and a number of adenosine analogues, N 6 -R-phenylisopropyladenosine (R-PIA), N 6 -cyclopentyladenosine (CPA) . We have also studied the e ects of endothelial removal and uptake inhibition by nitrobenzylthioinosine (NBTI) and the e ects of the A 3 receptor antagonist 1,3-dipropyl-8-(4-acrylate)phenylxanthine (BWA1433). 2 Adenosine, NECA, CPA and R-PIA all elicited relaxant responses in tissues precontracted with phenylephrine (1 mM) with the following potency order: NECA4R-PIA4adenosine=CPA. However, E/[A] curves to NECA were biphasic. CGS 21680 was inactive at concentrations up to 30 mM and IB-MECA elicited relaxant responses which were resistant to blockade by 8-SPT and BWA1433 (100 mM). 3 Removal of the endothelium produced a small but signi®cant decrease in the asymptote of the high potency phase of E/[A] curves to NECA with no change in p[A] 50 . E/[A] curves to adenosine were not altered by removal of the endothelium. However, there were small rightward shifts of E/[A] curves to CPA and R-PIA in the absence of endothelium. 4 Inhibition of uptake by NBTI (1 mM) had no e ect on E/[A] curves to NECA, CPA or R-PIA, but E/[A] curves to adenosine were signi®cantly left-shifted in the presence of NBTI. 5 8-SPT (10 ± 100 mM) caused signi®cant rightward shifts of the high potency phase of the E/[A] curves to NECA (pA 2 =5.63+0.26). The second phase of the concentration-response curve to NECA appeared to be resistant to blockade by 8-SPT, as were E/[A] curves for adenosine, CPA or R-PIA. However, in the presence of NBTI (1 mM), 8-SPT (100 mM) gave signi®cant rightward shifts of E/[A] curves to adenosine. 6 ZM 241385 (0.1 ± 1 mM) produced signi®cant rightward shifts of the high potency phase of NECA E/[A] curves (pA 2 =7.65+0.25 in the presence and 7.20+0.12 in the absence of endothelium), while curves to R-PIA were not signi®cantly shifted by 1 mM ZM 241385. In the presence of NBTI E/[A] curves to adenosine were signi®cantly rightward shifted by ZM 241385 (0.1 mM, pA 2 =7.50+0.16). 7 In conclusion, the results suggest activation of A 2B receptors located primarily on the smooth muscle by low concentrations of NECA and by adenosine under conditions of uptake blockade, and of another, as yet unde®ned site which may be intracellular, by higher concentrations of NECA, by CPA, R-PIA and adenosine under conditions where uptake is operational.,

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Section: Controlmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activation of two sites by adenosine receptor agonists to cause relaxation in rat isolated mesenteric artery

Prentice

Payne

Hourani

1997

British J Pharmacology

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“…N 6 -(3-iodobenzyl)-adenosine-5'-N-methylcarboxamide (IB-MECA) has been reported as a selective A 3 -receptor agonist (Jacobson et al, 1993;Gallo-RodrõÂ guez et al, 1994). A 3 -receptors are resistant to blockade with methylxanthines, although it has been reported that compounds such as 1,3-dipropyl-8-(4-acrylate)phenylxanthine (BWA1433) block them (Jacobson et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

A_2B adenosine receptors mediate relaxation of the pig intravesical ureter: adenosine modulation of non adrenergic non cholinergic excitatory neurotransmission

Hernández¹,

Barahona²,

Bustamante

et al. 1999

British J Pharmacology

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1 The present study was designed to characterize the adenosine receptors involved in the relaxation of the pig intravesical ureter, and to investigate the action of adenosine on the non adrenergic non cholinergic (NANC) excitatory ureteral neurotransmission. 2 In U46619 (10 77 M)-contracted strips treated with the adenosine uptake inhibitor, nitrobenzylthioinosine (NBTI, 10 76 M), adenosine and related analogues induced relaxations with the following potency order:

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“…Pharmacological studies, using antagonists to the different adenosine receptors, revealed that A3AR plays a key role in the adenosineinduced inhibition of tumour cell proliferation, simultaneously stimulating bone marrow cell growth (Fishman et al, 2000a, b;BarYehuda et al, 2001). Indeed, synthetic agonists to A3AR, such as CF101 and Cl-IB-MECA (Jacobson et al, 1995), were found to act similar to adenosine, while having the advantage of being stable, nondegradable, and bioavailable molecules (Fishman et al, 2000a, b).…”

mentioning

confidence: 99%

Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101

et al. 2003

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Adenosine is a purine nucleoside that acts as a regulatory molecule by binding to specific G-protein-coupled A1, A 2A , A 2B , and A3 cell surface receptors. We have recently demonstrated that adenosine inhibits tumour cell growth and concomitantly stimulates bone marrow cell proliferation via activation of the A3 adenosine receptor (A3AR). In the present study, we show that a synthetic agonist to the A3AR, CF101, at the low nanomolar concentration range, inhibits HCT-116 human colon carcinoma cell growth. This effect was reversed by the selective A3AR antagonist MRS1523, demonstrating the specificity of the response. CF101 (given orally) was efficacious in inhibiting the development of primary tumours in xenograft and syngeneic models in which mice were inoculated subcutaneously with human HCT-116 or murine CT-26 colon carcinoma cells, respectively. Moreover, CF101 suppressed (50%, Po0.01) colon cancer liver metastases in syngeneic mice inoculated to the spleen with CT-26 cells. The mechanism of action entailed upregulation of interleukin-12 production in the CF101-treated groups and potentiation of NK cell activity. In the HCT-116 xenograft model in which a combined therapy of CF101 and 5-fluorouracyl (5-FU) was examined, an additive antitumour effect was demonstrated. Moreover, CF101 prevented the 5-FU-induced myelotoxicity, resulting in normal values of white blood cell and neutrophil counts. We conclude that the A3AR agonist CF101, a small orally bioavailable molecule, exerts systemic anticancer, antimetastatic, and myeloprotective effects in colon carcinoma-bearing mice, and may serve as an adjuvant treatment to enhance the chemotherapeutic index and prevent myelotoxicity.

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A3-adenosine receptors: Design of selective ligands and therapeutic prospects

Cited by 122 publications

References 35 publications

Activation of two sites by adenosine receptor agonists to cause relaxation in rat isolated mesenteric artery

Activation of two sites by adenosine receptor agonists to cause relaxation in rat isolated mesenteric artery

A_2B adenosine receptors mediate relaxation of the pig intravesical ureter: adenosine modulation of non adrenergic non cholinergic excitatory neurotransmission

Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101

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A3-adenosine receptors: Design of selective ligands and therapeutic prospects

Cited by 122 publications

References 35 publications

Activation of two sites by adenosine receptor agonists to cause relaxation in rat isolated mesenteric artery

Activation of two sites by adenosine receptor agonists to cause relaxation in rat isolated mesenteric artery

A2B adenosine receptors mediate relaxation of the pig intravesical ureter: adenosine modulation of non adrenergic non cholinergic excitatory neurotransmission

Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101

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A_2B adenosine receptors mediate relaxation of the pig intravesical ureter: adenosine modulation of non adrenergic non cholinergic excitatory neurotransmission