期刊
BIOCHEMICAL PHARMACOLOGY
卷 65, 期 4, 页码 525-534出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0006-2952(02)01556-3
关键词
adenosine receptors; allosteric modulation; amiloride; sodium ions; cyclic AMP; receptor binding
资金
- Intramural NIH HHS [Z01 DK031117] Funding Source: Medline
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, [H-3]8-cyclopentyl-1,3-diproplxanthine ([H-3]DPCPX) and [H-3]8-ethyl-4-methyl-2-phenyl-(8R)-4,5,7,8-tetrahydro-1H-imidazo[2, 1-i]purin-5-one ([H-3]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 [H-3]N-6-[(R)-phenyhsopropyl]adenosine ([H-3]R-PIA) from A(1) receptors or the A(2A) agonist [H-3]2-[p-(2-carboxvethyl)phenyl-ethylamino]-5'-N-ethylearboxamidoadenosine ([H-3]CGS21680) from A(2A) receptors. The dissociation rate of the A(3) agonist radioligand [I-125]N-6-(4-amino-3-iodobenzyl)adenosine-5'-N-methyluronamide ([I-125]-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, (C) 2002 Elsevier Science Inc. All rights reserved.
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