Potent antagonists for the human adenosine A2B receptor. Derivatives of the triazolotriazine adenosine receptor antagonist ZM241385 with high affinity

Zwart, M. De; Vollinga, R C; Beukers, Margot W.; Sleegers, Danielle F.; Knzel, Jacobien K. von Frijtag Drabbe; Groote, Miriam de; Ijzerman, A. P.

doi:10.1002/(sici)1098-2299(199911)48:3<95::aid-ddr1>3.0.co;2-b

Cited by 55 publications

(53 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The kinetics of the association appeared monophasic with a T 1/2 value of 7.65 ± 0.28 min. At equilibrium, the nonspecific binding did not exceed 30% of the total value of 145 nM, somewhat less potent than previously determined [7,12]. Another potent xanthine derivative, XCC [14], which is a precursor of MRS 1754, had a K i value of 54 nM in binding to human A 2B receptors, similar to the value reported previously [12].…”

Section: Resultsmentioning

confidence: 99%

“…The pharmacological characteristics of this binding site resemble the functional characteristics of A 2B receptors [7,11,19,20,22] Theophylline is widely used as an antiasthmatic drug, although its mechanism of action is uncertain. The related xanthine enprofylline (3-propylxanthine) [9,13], which is also therapeutically efficacious in the treatment of asthma, was earlier thought to act through a non-adenosine receptor-mediated mechanism due to its low affinity at A 1 and A 2A receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of A 2B receptors in human retinal endothelial cells may lead to neovascularization by a mechanism involving increased angiogenic growth factor expression [5]. Selective xanthine antagonists of the A 2B receptor have been reported recently [6,7]. Such antagonists are potentially useful in the treatment of asthma [8,9] and intestinal disorders [10].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

[3H]MRS 1754, a selective antagonist radioligand for A2B adenosine receptors

Kim

Ahern³

et al. 2001

Biochemical Pharmacology

View full text Add to dashboard Cite

MRS 1754 [N-(4-cyanophenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy]acetamide] is a selective antagonist ligand of A 2B adenosine receptors. This is the least well-defined adenosine receptor subtype, and A 2B antagonists have potential as antiasthmatic drugs. For use as a radioligand, MRS 1754, a p-cyanoanilide xanthine derivative, was tritiated on the propyl groups in a two-step reaction using a p-carboxamido precursor, which was dehydrated to the cyano species using trifluoroacetic anhydride.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

[3H]MRS 1754, a selective antagonist radioligand for A2B adenosine receptors

Kim

Ahern³

et al. 2001

Biochemical Pharmacology

View full text Add to dashboard Cite

show abstract

“…The prototypic, albeit nonselective, agonist for this receptor is 5Ј-N-ethylcarboxamidoadenosine (NECA). In contrast, several high-affinity antagonists have been developed for this receptor (Kim et al, 1998, De Zwart et al, 1999b. The most selective and potent antagonist currently available is MRS1754 (Kim et al, 2000).…”

mentioning

confidence: 96%

Random Mutagenesis of the Human Adenosine A_2B Receptor Followed by Growth Selection in Yeast. Identification of Constitutively Active and Gain of Function Mutations

Beukers

Oppenraaij²,

Hoorn³

et al. 2004

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

To gain insight in spontaneous as well as agonist-induced activation of the human adenosine A 2B receptor, we applied a random mutagenesis approach in yeast to create a large number of receptor mutants and selected mutants of interest with a robust screening assay based on growth. The amino acid sequence of 14 mutated receptors was determined. All these mutated receptors displayed constitutive activity. In particular, single-point mutations at T42A, V54L, and F84S and a triplepoint mutation at N36S, T42A, and T66A resulted in high constitutive activity. In addition, a C-terminally truncated (after Lys269) mutant, Q214L I230N V240M V250M N254Y T257S K269stop, was highly constitutively active. The T42A, V54L, and F84S mutants showed a considerable decrease, 4.9-to 6.9-fold, in the EC 50 value of 5Ј-N-ethylcarboxamidoadenosine (NECA), an adenosine analog. Combined mutation of I242T, K269R, V284A, and H302Q, as well as F84L together with S95G, resulted in an even greater potency of NECA of 10-and 18-fold, respectively. In fact, all constitutively active mutants had an increased potency for NECA. This suggests that the wild-type (wt) human A 2B receptor itself is rather silent, which may explain the low affinity of agonists for this receptor. To verify the ability of the mutant receptors to activate mammalian second messenger systems, cAMP experiments were performed in CHO cells stably expressing the wt and T42A receptors. These experiments confirmed the increased sensitivity of T42A for NECA, because the EC 50 values of T42A and the wt receptor were 0.15 Ϯ 0.04 and 1.3 Ϯ 0.4 M, respectively.

show abstract

“…Table II shows a number of ZM241385 derivatives. In all cases, a high degree of selectivity for the A 1 AR, A 2B AR, and A 2A AR receptors over the A 3 AR is observed, in agreement with the lower conservation of binding site residues observed at the A 3 AR (De Zwart et al, 1999). However, a phenylethylamine substituent shows no selectivity across the A 1 AR, A 2A AR, and A 2B AR receptors.…”

Section: The Structure Of Adenosine Receptorsmentioning

confidence: 99%

The Structure of the Adenosine Receptors

Lane

Jaakola

IJzerman

2011

Advances in Pharmacology

View full text Add to dashboard Cite

Potent antagonists for the human adenosine A2B receptor. Derivatives of the triazolotriazine adenosine receptor antagonist ZM241385 with high affinity

Cited by 55 publications

References 23 publications

[3H]MRS 1754, a selective antagonist radioligand for A2B adenosine receptors

[3H]MRS 1754, a selective antagonist radioligand for A2B adenosine receptors

Random Mutagenesis of the Human Adenosine A_2B Receptor Followed by Growth Selection in Yeast. Identification of Constitutively Active and Gain of Function Mutations

The Structure of the Adenosine Receptors

Contact Info

Product

Resources

About

Potent antagonists for the human adenosine A2B receptor. Derivatives of the triazolotriazine adenosine receptor antagonist ZM241385 with high affinity

Cited by 55 publications

References 23 publications

[3H]MRS 1754, a selective antagonist radioligand for A2B adenosine receptors

[3H]MRS 1754, a selective antagonist radioligand for A2B adenosine receptors

Random Mutagenesis of the Human Adenosine A2B Receptor Followed by Growth Selection in Yeast. Identification of Constitutively Active and Gain of Function Mutations

The Structure of the Adenosine Receptors

Contact Info

Product

Resources

About

Random Mutagenesis of the Human Adenosine A_2B Receptor Followed by Growth Selection in Yeast. Identification of Constitutively Active and Gain of Function Mutations