A<sub>3</sub>adenosine receptor knockout mice are protected against ischemia- and myoglobinuria-induced renal failure

Lee, H. Thomas; Ota‐Setlik, Ayuko; Xu, Huimin; D’Agati, Vivette D.; Jacobson, Marlene A.; Emala, Charles W.

doi:10.1152/ajprenal.00271.2002

Cited by 90 publications

(93 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to the effect of AR activation on the heart, pretreatment with an A 1 agonist or an A 3 antagonist protects the kidney from a subsequent prolonged ischemic insult [28]. The role of the A 3 AR in kidney function was further confirmed by the fact that A 3 AR knockout mice are protected against ischemia-and myoglobinuria-induced renal failure [29]. Hence, dual-acting compounds (activating A 1 and blocking A 3 ARs), such as CCPA, might be useful for protection of ischemic condition of kidney.…”

Section: Discussionmentioning

confidence: 99%

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

Gao

Jeong

Moon

et al. 2004

Biochemical Pharmacology

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: Discussionmentioning

confidence: 99%

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

Gao

Jeong

Moon

et al. 2004

Biochemical Pharmacology

View full text Add to dashboard Cite

show abstract

“…Restoration after ischaemia by perfusion of ATP-MgCl 2 was described early [104,335]. A 3 receptor knock-out mice are protected against ischaemic renal failure [208]. Ischaemia remodels filamentous actin leading to desquamation of proximal tubular epithelial cells via ATP depletion-induced p38 MAPK-HSP27 signalling [72].…”

Section: Ischaemiamentioning

confidence: 99%

Purinergic signalling in the kidney in health and disease

Burnstock

Evans

Bailey

2013

Purinergic Signalling

View full text Add to dashboard Cite

The involvement of purinergic signalling in kidney physiology and pathophysiology is rapidly gaining recognition and this is a comprehensive review of early and recent publications in the field. Purinergic signalling involvement is described in several important intrarenal regulatory mechanisms, including tuboglomerular feedback, the autoregulatory response of the glomerular and extraglomerular microcirculation and the control of renin release. Furthermore, purinergic signalling influences water and electrolyte transport in all segments of the renal tubule. Reports about purine-and pyrimidine-mediated actions in diseases of the kidney, including polycystic kidney disease, nephritis, diabetes, hypertension and nephrotoxicant injury are covered and possible purinergic therapeutic strategies discussed.

show abstract

“…ARTICLE AR subtype of all of the compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) reported in this work.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 98%

“…Interest for this new series was driven by the structural similarity between the PHTZ skeleton and both the 2-aryl-1,2,4-triazolo [4,3-a]quinoxalin-1-one (TQX) and the 4-carboxamido-quinazoline (QZ) scaffolds extensively investigated in our previously reported studies. Our attention was focused at position 4 of the phthalazine nucleus where different amido and ureido moieties were introduced (compounds [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Some of the new PHTZ compounds showed high hA 3 AR affinity and selectivity, the 2,5-dimethoxyphenylphthalazin-1(2H)-one 18 being the most potent and selective hA 3 AR antagonist among this series (K i = 0.776 nM; hA 1 / hA 3 and hA 2A /hA 3 > 12000).…”

Section: ' Introductionmentioning

confidence: 99%

“…9 Thus, numerous A 3 AR agonists and antagonists have been investigated for their potential therapeutic applications 7,[9][10][11][12][14][15][16][17] and to shed light on which could be the best choice for a given disease. It is easy to understand why we have directed our efforts in this intriguing direction and why, in the past few years, our attention has been focused on the development of adenosine A 3 receptor antagonists.…”

Section: ' Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Identification of the 2-Phenylphthalazin-1(2H)-one Scaffold as a New Decorable Core Skeleton for the Design of Potent and Selective Human A₃ Adenosine Receptor Antagonists

et al. 2011

View full text Add to dashboard Cite

A₃adenosine receptor knockout mice are protected against ischemia- and myoglobinuria-induced renal failure

Abstract: adenosine receptor knockout mice are protected against ischemia-and myoglobinuria-induced renal failure.

Cited by 90 publications

References 26 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

Purinergic signalling in the kidney in health and disease

The Identification of the 2-Phenylphthalazin-1(2H)-one Scaffold as a New Decorable Core Skeleton for the Design of Potent and Selective Human A₃ Adenosine Receptor Antagonists

Contact Info

Product

Resources

About

A3adenosine receptor knockout mice are protected against ischemia- and myoglobinuria-induced renal failure

Abstract: adenosine receptor knockout mice are protected against ischemia-and myoglobinuria-induced renal failure.

Cited by 90 publications

References 26 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

Purinergic signalling in the kidney in health and disease

The Identification of the 2-Phenylphthalazin-1(2H)-one Scaffold as a New Decorable Core Skeleton for the Design of Potent and Selective Human A3 Adenosine Receptor Antagonists

Contact Info

Product

Resources

About

A₃adenosine receptor knockout mice are protected against ischemia- and myoglobinuria-induced renal failure

The Identification of the 2-Phenylphthalazin-1(2H)-one Scaffold as a New Decorable Core Skeleton for the Design of Potent and Selective Human A₃ Adenosine Receptor Antagonists