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Biochem Pharmacol. 2000 Sep 1;60(5):669-76.

Allosteric modulation of A(2A) adenosine receptors by amiloride analogues and sodium ions.

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Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.


Allosteric regulation of rat A(2A) adenosine receptors by amiloride, amiloride analogues, and sodium ions was studied by investigating their ability to influence the dissociation of [(3)H]4-2-[7-amino-2-(2-furyl)-1,2,4-triazolo[1,5-a][1,3, 5]triazin-5-yl-amino]ethylphenol ([(3)H]ZM241385) from receptors in rat striatal membranes. Both amiloride and its analogues accelerated the dissociation, the analogues being more potent than amiloride itself. In contrast, sodium ions decreased the rate of [(3)H]ZM241385 dissociation in a concentration-dependent manner, and this rate was not influenced by guanosine triphosphate, N-ethylmaleimide, suramin, or the selective A(2A) adenosine receptor antagonist, 5-amino-2-(2-furyl)-7(2-phenylethyl)pyrazolo[4,3-e]-1,2, 4-triazolo[1,5-c]pyrimidine (SCH58261). The effect of competition between the amiloride analogue 5-(N,N-hexamethylene)amiloride (HMA) and sodium ions on [(3)H]ZM241385 dissociation was also explored. The addition of sodium ions resulted in a concentration-dependent rightward shift of the HMA response curve. The slopes of the HMA concentration-response curves in the presence and absence of sodium ions were not significantly different, which suggests that sodium ions and amiloride analogues act at a common allosteric site on the A(2A) adenosine receptor. There was a lack of correlation between the displacement of ligand binding and the allosteric potencies of the amiloride analogues.

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