A physiological role of the adenosine A
            <sub>3</sub>
            receptor: Sustained cardioprotection

Liang, Bruce T.

doi:10.1073/pnas.95.12.6995

Cited by 197 publications

(153 citation statements)

References 19 publications

Supporting

Mentioning

149

Contrasting

Order By: Relevance

“…In an effort to develop potent agonists and antagonists for A 3 ARs, a wide range of N 6 -and 2′-substituted adenosine derivatives have recently been pharmacologically characterized [8][9][10]. We found that various adenosine derivatives, which were previously demonstrated to be agonists at A 1 and A 2A ARs and assumed to be full/partial agonists at A 3 ARs, are indeed antagonists at this subtype.…”

Section: Introductionmentioning

confidence: 78%

“…For A 3 AR binding experiments, the procedures used were similar to those previously described [17]. Briefly, each tube contained 100 μL of membrane suspension (20 μg protein), 50 μL of [ 125 I]I-AB-MECA (final concentration 1.0 nM), and 50 μL of increasing concentrations of compounds in Tris-HCl buffer (50 mM, pH 8.0) containing 10 mM MgCl 2 , 1 mM EDTA.…”

Section: Radioligand Binding Assaymentioning

confidence: 99%

“…The selective activation of A 3 ARs has been demonstrated to be both cardioprotective [3,4] and cerebroprotective [5,6]. Both selective agonists and antagonists [7] for A 3 ARs are of potential clinical use.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, the efficacy of adenosine derivatives appears to be more dependent on small structural changes at the A 3 AR than at other subtypes. Structural determinants critically involved in A 3 AR activation have been identified [8][9][10][11][12][13], leading to the conclusion that the ability of an adenosine derivative to activate the A 3 AR tends to be highly structure-sensitive. 3′-Fluoro has recently been found to interfere with A 3 AR binding [14], and certain 4′-thio nucleosides have been found to be potent and selective human A 3 AR agonists [15].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety

Gao

Jeong

Moon

et al. 2004

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

We have found previously that structural features of adenosine derivatives, particularly at the N 6 -and 2-positions of adenine, determine the intrinsic efficacy as A 3 adenosine receptor (AR) agonists. Here, we have probed this phenomenon with respect to the ribose moiety using a series of ribose-modified adenosine derivatives, examining binding affinity and activation of the human A 3 AR expressed in CHO cells. Both 2′-and 3′-hydroxyl groups in the ribose moiety contribute to A 3 AR binding and activation, with 2′-OH being more essential. Thus, the 2′-fluoro substitution eliminated both binding and activation, while a 3′-fluoro substitution led to only a partial reduction of potency and efficacy at the A 3 AR. A 5′-uronamide group, known to restore full efficacy in other derivatives, failed to fully overcome the diminished efficacy of 3′-fluoro derivatives. The 4′-thio substitution, which generally enhanced A 3 AR potency and selectivity, resulted in 5′-CH 2 OH analogues (10 and 12) which were partial agonists of the A 3 AR. Interestingly, the shifting of the N 6 -(3-iodobenzyl)adenine moiety from the 1′-to 4′-position had a minor influence on A 3 AR selectivity, but transformed 15 into a potent antagonist (16) (K i = 4.3 nM). Compound 16 antagonized human A 3 AR agonist-induced inhibition of cyclic AMP with a K B value of 3.0 nM. A novel apio analogue (20) of neplanocin A, was a full A 3 AR agonist. The affinities of selected, novel analogues at rat ARs were examined, revealing species differences. In summary, critical structural determinants for human A 3 AR activation have been identified, which should prove useful for further understanding the mechanism of receptor activation and development of more potent and selective full agonists, partial agonists and antagonists for A 3 ARs.

show abstract

Section: Introductionmentioning

confidence: 78%

Section: Radioligand Binding Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety

Gao

Jeong

Moon

et al. 2004

Biochemical Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…13 Cardioprotection by selective A 3 AR agonists has been extensively explored in various species. [14][15][16] Other selective A 3 AR agonists have recently been reported, based on introduction of large substituents at the N 6 and C2 positions and modification of the ribose ring, particularly at the 4′ and 5′ positions. 16-19 For example, the 4′ -thio analogue 2 is among the most selective known A 3 AR agonists,17 and 3′ -amino substitution is possible.…”

mentioning

confidence: 99%

Design of (N)-methanocarba adenosine 5′-uronamides as species-independent A3 receptor-selective agonists

Melman

Gao

Kumar

et al. 2008

Bioorganic & Medicinal Chemistry Letters

Self Cite

View full text Add to dashboard Cite

Abstract2-Chloro-5′ -N-methylcarboxamidoadenosine analogues containing the (N)-methanocarba (bicyclo [3.1.0]hexane) ring system as a ribose substitute display increased selectivity as agonists of the human A 3 adenosine receptor (AR). However, the selectivity in mouse was greatly reduced due to an increased tolerance of this ring system at the mouse A 1 AR. Therefore, we varied substituents at the N 6 and C2 positions in search of compounds that have improved A 3 AR selectivity and are species independent. An N 6 -methyl analogue was balanced in affinity at mouse A 1 /A 3 ARs, with high selectivity in comparison to the A 2A AR. Substitution of the 2-chloro atom with larger and more hydrophobic substituents, such as iodo and alkynyl groups, tended to increase the A 3 AR selectivity (up to 430-fold) in mouse and preserve it in human. Extended and chemically functionalized alkynyl chains attached at the C2 position of the purine moiety preserved A 3 AR selectivity more effectively than similar chains attached at the 3 position of the N 6 -benzyl group. Keywordsnucleoside; G protein-coupled receptor; mouse; adenosine receptor; radioligand binding Adenosine is a protective mediator that has been described as a general endogenous signal for tissue protection and regeneration and even "the signal of life". 1,2 Adenosine activates four different receptor subtypes -A 1 , A 2A , A 2B , and A 3 -which are widely but differentially distributed throughout the body. 3 The A 3 adenosine receptor (AR) is located in some neurons, astrocytes, various immune cell populations (neutrophils, eosinophils, mast cells) and potentially muscle cells and endothelial cells. 4-7 The A 3 AR is coupled to inhibition of adenylate cyclase and also activates Akt and calcium mobilization. 8,9 Two potent and selective agonists of the A 3 AR, IB-MECA 1a and Cl-IB-MECA 1b, are currently in Phase II clinical trials for the treatment of rheumatoid arthritis, several other autoimmune inflammatory diseases, and cancer. 10-12 Protective mechanisms in the envisioned disease applications of A 3 AR agonists appear to be a downregulation of the NF-κB system, common to both arthritis and cancer treatments, 12 and a widespread correction of gene dysregulation induced in an Corresponding author: Dr. K.A. Jacobson, Chief, Molecular Recognition Section, Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC, Bethesda, MD 20892-0810. Tel: 301-496-9024. Fax: 301-480-8422; Email: kajacobs@helix.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. .0]hexane) nucleoside analogues were used to determine that the biologically active conformat...

show abstract

A3 Adenosine Receptor Ligands: History and Perspectives

et al. 2000

View full text Add to dashboard Cite

Adenosine regulates many physiological functions through specific cell membrane receptors. On the basis of pharmacological studies and molecular cloning, four different adenosine receptors have been identified and classified as A1, A2A, A2B, and A3. These adenosine receptors are members of the G‐protein‐coupled receptor family. While adenosine A1 and A2A receptor subtypes have been pharmacologically characterized through the use of selective ligands, the A3 adenosine receptor subtype is presently under study in order to better understand its physio‐pathological functions. Activation of adenosine A3 receptors has been shown to stimulate phospholipase C and D and to inhibit adenylate cyclase. Activation of A3 adenosine receptors also causes the release of inflammatory mediators such as histamine from mast cells. These mediators are responsible for processes such as inflammation and hypotension. It has also been suggested that the A3 receptor plays an important role in brain ischemia, immunosuppression, and bronchospasm in several animal models. Based on these results, highly selective A3 adenosine receptor agonists and/or antagonists have been indicated as potential drugs for the treatment of asthma and inflammation, while highly selective agonists have been shown to possess cardioprotective effects. The updated material related to this field of research has been rationalized and arranged in order to offer an overview of the topic. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 2, 103–128, 2000

show abstract

A physiological role of the adenosine A ₃ receptor: Sustained cardioprotection

Cited by 197 publications

References 19 publications

Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety

Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety

Design of (N)-methanocarba adenosine 5′-uronamides as species-independent A3 receptor-selective agonists

A3 Adenosine Receptor Ligands: History and Perspectives

Contact Info

Product

Resources

About

A physiological role of the adenosine A 3 receptor: Sustained cardioprotection

Cited by 197 publications

References 19 publications

Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety

Structural determinants of efficacy at A3 adenosine receptors: modification of the ribose moiety

Design of (N)-methanocarba adenosine 5′-uronamides as species-independent A3 receptor-selective agonists

A3 Adenosine Receptor Ligands: History and Perspectives

Contact Info

Product

Resources

About

A physiological role of the adenosine A ₃ receptor: Sustained cardioprotection