PT  - JOURNAL ARTICLE
AU  - Gao, Zhan-Guo
AU  - Kim, Seong Gon
AU  - Soltysiak, Kelly A.
AU  - Melman, Neli
AU  - IJzerman, Adriaan P.
AU  - Jacobson, Kenneth A.
TI  - Selective Allosteric Enhancement of Agonist Binding and Function at Human A<sub>3</sub> Adenosine Receptors by a Series of Imidazoquinoline Derivatives
AID  - 10.1124/mol.62.1.81
DP  - 2002 Jul 01
TA  - Molecular Pharmacology
PG  - 81--89
VI  - 62
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/62/1/81.short
4100  - http://molpharm.aspetjournals.org/content/62/1/81.full
SO  - Mol Pharmacol2002 Jul 01; 62
AB  - 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.