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Research ArticleArticle

Selective Allosteric Enhancement of Agonist Binding and Function at Human A3 Adenosine Receptors by a Series of Imidazoquinoline Derivatives

Zhan-Guo Gao, Seong Gon Kim, Kelly A. Soltysiak, Neli Melman, Adriaan P. IJzerman and Kenneth A. Jacobson
Molecular Pharmacology July 2002, 62 (1) 81-89; DOI: https://doi.org/10.1124/mol.62.1.81
Zhan-Guo Gao
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Seong Gon Kim
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Kelly A. Soltysiak
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Neli Melman
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Adriaan P. IJzerman
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Kenneth A. Jacobson
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Abstract

We have identified a series of 1H-imidazo-[4,5-c]quinolines as selective allosteric enhancers of human A3 adenosine receptors. Several of these compounds potentiated both the potency and maximal efficacy of agonist-induced responses and selectively decreased the dissociation of the agonistN 6-(4-amino-3-[125I]iodobenzyl)-5′-N-methylcarboxamidoadenosine from human A3 adenosine receptors. There was no effect on the dissociation of the antagonist [3H]8-ethyl-4-methyl-2-phenyl-(8R)-4,5,7,8-tetrahydro-1H-imidazo[2.1-i]purin-5-one (PSB-11) from the A3 receptors, as well as [3H]N 6-[(R)-phenylisopropyl]adenosine from rat brain A1 receptors and [3H]2-[p-(2-carboxyethyl)phenyl-ethylamino]-5′-N-ethylcarboxamidoadenosine from rat striatal A2A receptors, suggesting the selective enhancement of agonist binding at A3 receptors. The analogs were tested as antagonists of competitive binding at human A3 receptors, and K i values ranging from 120 nM to 101 μM were observed; as for many allosteric modulators of G protein-coupled receptors, an orthosteric effect was also present. The most promising leads from the present set of analogs seem to be the 2-cyclopentyl-1H-imidazo[4,5-c]quinoline derivatives, of which the 4-phenylamino analog DU124183 had the most favorable degree of allosteric modulation versus receptor antagonism. The inhibition of forskolin-stimulated cyclic AMP accumulation in intact cells that express human A3 receptors was employed as a functional index of A3 receptor activation. The enhancer DU124183 caused a marked leftward shift of the concentration-response curve of the A3 receptor agonists in the presence of antagonist and, surprisingly, a potentiation of the maximum agonist efficacy by approximately 30%. Thus, we have identified a novel structural lead for developing allosteric enhancers of A3 adenosine receptors; such enhancers may be useful for treating brain ischemia and other hypoxic conditions.

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Molecular Pharmacology: 62 (1)
Molecular Pharmacology
Vol. 62, Issue 1
1 Jul 2002
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Research ArticleArticle

Selective Allosteric Enhancement of Agonist Binding and Function at Human A3 Adenosine Receptors by a Series of Imidazoquinoline Derivatives

Zhan-Guo Gao, Seong Gon Kim, Kelly A. Soltysiak, Neli Melman, Adriaan P. IJzerman and Kenneth A. Jacobson
Molecular Pharmacology July 1, 2002, 62 (1) 81-89; DOI: https://doi.org/10.1124/mol.62.1.81

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Research ArticleArticle

Selective Allosteric Enhancement of Agonist Binding and Function at Human A3 Adenosine Receptors by a Series of Imidazoquinoline Derivatives

Zhan-Guo Gao, Seong Gon Kim, Kelly A. Soltysiak, Neli Melman, Adriaan P. IJzerman and Kenneth A. Jacobson
Molecular Pharmacology July 1, 2002, 62 (1) 81-89; DOI: https://doi.org/10.1124/mol.62.1.81
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