Differential allosteric modulation by amiloride analogues of agonist and antagonist binding at A1 and A3 adenosine receptors
| Autor: | Seong Gon Kim, Adriaan P. IJzerman, Neli Melman, Andreas A. Erdmann, Christa E. Müller, Kenneth A. Jacobson, Zhan-Guo Gao |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Agonist
Adenosine Receptor Adenosine A2A Stereochemistry medicine.drug_class Allosteric regulation CHO Cells Pharmacology Transfection Tritium Biochemistry Article Amiloride Radioligand Assay Allosteric Regulation Cricetinae Phenethylamines Cyclic AMP Purinergic P1 Receptor Agonists medicine Radioligand Animals Humans Drug Interactions Diuretics Receptor Dose-Response Relationship Drug Chemistry Colforsin Receptor Adenosine A3 Imidazoles Receptors Purinergic P1 Adenosine receptor Kinetics Purinergic P1 Receptor Antagonists Purines Xanthines medicine.drug |
| Zdroj: | Biochem Pharmacol |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/s0006-2952(02)01556-3 |
| Popis: | The diuretic drug amiloride and its analogues were found previously to be allosteric modulators of antagonist binding to A(2A) adenosine receptors. In this study, the possibility of the allosteric modulation by amiloride analogues of antagonist binding at A(1) and A(3) receptors, as well as agonist binding at A(1), A(2A), and A(3) receptors, was explored. Amiloride analogues increased the dissociation rates of two antagonist radioligands, [(3)H]8-cyclopentyl-1,3-dipropylxanthine ([(3)H]DPCPX) and [(3)H]8-ethyl-4-methyl-2-phenyl-(8R)-4,5,7,8-tetrahydro-1H-imidazo[2,1-i]purin-5-one ([(3)H]PSB-11), from A(1) and A(3) receptors, respectively. Amiloride and 5-(N,N-dimethyl)amiloride (DMA) were more potent at A(1) receptors than at A(3) receptors, while 5-(N,N-hexamethylene)amiloride (HMA) was more potent at A(3) receptors. Thus, amiloride analogues are allosteric inhibitors of antagonist binding at A(1), A(2A), and A(3) adenosine receptor subtypes. In contrast to their effects on antagonist-occupied receptors, amiloride analogues did not affect the dissociation rates of the A(1) agonist [(3)H]N(6)-[(R)-phenylisopropyl]adenosine ([(3)H]R-PIA) from A(1) receptors or the A(2A) agonist [(3)H]2-[p-(2-carboxyethyl)phenyl-ethylamino]-5′-N-ethylcarboxamidoadenosine ([(3)H]CGS21680) from A(2A) receptors. The dissociation rate of the A(3) agonist radioligand [(125)I]N(6)-(4-amino-3-iodobenzyl)-adenosine-5′-N-methyluronamide ([(125)I]I-AB-MECA) from A(3) receptors was decreased significantly by amiloride analogues. The binding modes of amiloride analogues at agonist-occupied and antagonist-occupied receptors differed markedly, which was demonstrated in all three subtypes of adenosine receptors tested in this study. The effects of the amiloride analogues on the action of the A(3) receptor agonist were explored further using a cyclic AMP functional assay in intact CHO cells expressing the human A(3) receptor. Both binding and functional assays support the allosteric interactions of amiloride analogues with A(3) receptors. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect