Allosteric modulation of the rat adenosine A<sub>1</sub> receptor: Differential effects on agonist and antagonist binding

Kourounakis, Angeliki P.; Visser, Corine C.; Groote, Miriam de; Ijzerman, A. P.

doi:10.1002/ddr.1

Cited by 10 publications

(7 citation statements)

References 24 publications

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“…However, several residues have been demonstrated to be critical to the modulation of either PD 81,723 or sodium ions. The mutation of Thr277 (7.42) to Ala not only decreased agonist affinity but also inhibited the effects of PD 81,723 [23]. Studies of the D55A 2.50 mutant A 1 AR revealed that Asp55 is responsible for allosteric regulation of binding by sodium because the affinity for [ 3 H]CCPA did not change over broad ranges of sodium concentrations [22].…”

Section: A 1 Arsmentioning

confidence: 99%

Allosteric Modulation of the Adenosine Family of Receptors

Gao¹,

Kim²,

IJzerman³

2005

MRMC

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Allosteric modulators for adenosine receptors (ARs) are of an increasing interest and may have potential therapeutic advantage over orthosteric ligands. Benzoylthiophene derivatives (including PD 81,723), 2-aminothiazolium salts, and related allosteric modulators of the A 1 AR have been studied. The benzoylthiophene derivatives were demonstrated to be selective enhancers for the A 1 AR, with little or no effect on other subtypes of ARs. Allosteric modulation of the A 2A AR has also been reported. A 3 allosteric enhancers may be predicted to be useful against ischemic conditions. We have recently characterized two classes of A 3 AR allosteric modulators: 3-(2-pyridinyl)isoquinolines (e.g. VUF5455) and 1H-imidazo-[4,5-c]quinolin-4-amines (e.g. DU124183), which selectively decreased the agonist dissociation rate at the human A 3 AR but not at A 1 and A 2A ARs. DU124183 left-shifted the agonist conc.-response curve for inhibition of forskolin-stimulated cAMP accumulation in intact cells expressing the human A 3 AR with up to 30% potentiation of the maximal efficacy. The increased potency of A 3 agonists was evident only in the presence of an A 3 antagonist, since VUF5455 and DU124183 also antagonized, i.e. displaced binding at the orthosteric site, with K i values of 1.68 and 0.82 μM, respectively. A 3 AR mutagenesis studies implicated F182 5.43 and N274 7.45 in the action of the enhancers and was interpreted using a rhodopsin-based A 3 AR molecular model, suggesting multiple binding modes. Amiloride analogues, SCH-202676 (N-(2,3-diphenyl-1,2,4-thiadiazol-5(2H)-ylidene)methanamine), and sodium ions were demonstrated to be common allosteric modulators for at least three subtypes (A 1 , A 2A , and A 3 ) of ARs.

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Section: A 1 Arsmentioning

confidence: 99%

Allosteric Modulation of the Adenosine Family of Receptors

Gao¹,

Kim²,

IJzerman³

2005

MRMC

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“…Diabetes mellitus is a condition characterized by chronically elevated levels of blood glucose caused by incorrect function of the hormone responsible for the hGCRG activation. Because the structure-based drug design program through substituted 2aminothiophenes has been investigated broadly, up to this date there are many other research works dealing with the synthesis, pharmacology and application of thiophenebased structures in medicinal chemistry (KOUROUNAKIS et al, 2000). It is no doubt, that this area of Gewald-like thiophene derivatives exhibits the highest progress in a scope and utilization.…”

Section: Other Important Pharmaceuticals Developed From2-aminothiophenesmentioning

confidence: 99%

Applications substituted 2-aminothiophenes in drug design

Puterová

Krutošíková

Végh

2021

Nova Biotechnol. Chim.

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Highly substituted thiophene derivatives are important heterocycles found in numerous biologically active compounds. Title compounds are attractive derivatives because their applications in pharmaceuticals, agriculture and pesticides. They exhibit antimicrobial activity against various Gram(+) and Gram(-) bacteria and fungi. Many of these molecules act as allosteric enhancers of A1-adenosine receptor, glucagon antagonists as well as antioxidant and anti-inflammatory agents.

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“…The synthesis of these latter two series of compounds is described in Scheme . The preparation of alkylated piperidones 12 − 18 was performed following the procedure of IJzerman,18a which consists of the reaction of the commercially available hydrochloric salt of 4-piperidone with the appropriate substituted benzyl chloride. For the synthesis of N -[(3-pyridyl)methyl]-4-piperidone 21 , acylation of 4-piperidone ethylene acetal with nicotinoyl chloride produced the amide 19 in good yield.…”

Section: Chemistrymentioning

confidence: 99%

“…To study the role of various substitutions on the phenyl ring and the importance of the 4,5-dimethyl group on the thienyl ring, Baraldi, IJzerman, and Tranberg 19 have described the synthesis and biological evaluation of mostly novel PD 81,723 analogues. It was evident from previous SAR studies that substitution with electron-withdrawing substituents, such as chlorine and trifluoromethyl, on the benzoyl moiety at the 3-position of the thiophene ring resulted in higher enhancement activity. − …”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Effects of Novel 2-Amino-3-naphthoylthiophenes as Allosteric Enhancers of the A₁Adenosine Receptor

et al. 2003

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The current study describes the synthesis and biological evaluation of a novel series of 2-amino-3-naphthoylthiophenes, with variable modifications at the 4- and 5-position of the thiophene as well as the naphthoyl ring. Allosteric enhancer activity was measured in several ways: (1) evaluating the effect on forskolin-stimulated cAMP accumulation in the presence of an A(1)-adenosine agonist (CPA) in Chinese hamster ovary (CHO) cells expressing the cloned human A(1)-adenosine receptor (hA(1)AR); (2) ability of these compounds to displace the binding of [(3)H]DPCPX, [(3)H]ZM 241385, and [(3)H]MRE 3008F20 to the ligand binding site of CHO cells expressing the hA(1), hA(2A), and hA(3) adenosine receptors, respectively; (3) effect on the binding of [(3)H]CCPA to membranes from CHO cells expressing hA(1)AR, to rat brain and human cortex membrane preparations containing native adenosine A(1) receptors; (4) kinetics of the dissociation of [(3)H]CCPA from CHO-hA1 membranes. The pharmacological assays compared the various activities to that of the reference compound PD 81,723 (compound 1). Several compounds appeared to be better than PD 81,723 to enhance the effect of CPA (and thus reduce cAMP content) in the CHO:hA(1) assay. The effect of these compounds at a concentration of 10 microM was slightly greater than that of the same concentration of the PD 81,723 and substantially greater than that of PD 81,723 when responses to 1 microM of each compound were compared. These include compounds 23, 25-29, 31-34, 38, 39, 43, and 58. Cycloalkylthiophenes tended to be more potent then their 4,5-dimethyl analogues, and in the series of cycloalkylthiophenes, tetrahydrobenzo[b]thiophene derivatives appeared to be more potent than the dihydrocyclopentadien[b]thiophene counterparts. Some of the most potent compounds were tested at a concentration of 10 microM for their affinity as competitors to the antagonist binding site of CHO cells expressing hA(1), hA(2A), and hA(3) adenosine receptors. None inhibited binding at the hA(2A)AR, but most of them inhibited binding to the hA(1)AR to varying extents (0-19%) as well as to the hA(3)AR to a substantial degree (0-57%). At a concentration of 10 microM, the compounds 31, 34, 37, 38, and 39 were more active than PD 81,723 to increase the binding of [(3)H]CCPA to CHO:hA(1), human brain and rat cortex membranes. Compound 37 was the most active compound increasing the binding to CHO:hA(1), human brain, and rat cortex membranes by 149, 43, and 27%, respectively (51, 15, and 22%, respectively, for PD 81,723). A good correlation was found between the increments [(3)H]CCPA binding to A(1) receptors expressed in different systems. Unlike the effect on agonist binding, the tested compounds did not increase the binding of the antagonist [(3)H]DPCPX on hCHO-A(1) membranes. Ligand dissociation studies revealed that two compounds (22 and 39) were more potent than 1 to slow the dissociation of [(3)H]CCPA from CHO:hA(1)AR membranes. No clear-cut structure-activity relationship can be observed based on data fro...

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Allosteric modulation of the rat adenosine A₁ receptor: Differential effects on agonist and antagonist binding

Cited by 10 publications

References 24 publications

Allosteric Modulation of the Adenosine Family of Receptors

Allosteric Modulation of the Adenosine Family of Receptors

Applications substituted 2-aminothiophenes in drug design

Synthesis and Biological Effects of Novel 2-Amino-3-naphthoylthiophenes as Allosteric Enhancers of the A₁Adenosine Receptor

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Allosteric modulation of the rat adenosine A1 receptor: Differential effects on agonist and antagonist binding

Cited by 10 publications

References 24 publications

Allosteric Modulation of the Adenosine Family of Receptors

Allosteric Modulation of the Adenosine Family of Receptors

Applications substituted 2-aminothiophenes in drug design

Synthesis and Biological Effects of Novel 2-Amino-3-naphthoylthiophenes as Allosteric Enhancers of the A1Adenosine Receptor

Contact Info

Product

Resources

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Allosteric modulation of the rat adenosine A₁ receptor: Differential effects on agonist and antagonist binding

Synthesis and Biological Effects of Novel 2-Amino-3-naphthoylthiophenes as Allosteric Enhancers of the A₁Adenosine Receptor