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Author Mettey, Y. ♦ Vierfond, J. M. ♦ Hanrahan, J. W. ♦ Gola, M. ♦ Verrier, B. ♦ Becq, F. ♦ Chappe, V.
Source PubMed Central
Content type Text
File Format PDF
Date Created 2005-01-28
Copyright Year ©1998
Language English
Difficulty Level Medium
Subject Domain (in DDC) Technology ♦ Medicine & health
Subject Keyword Pharmacology
Abstract On the basis of their structure, we compared the ability of 35 xanthine derivatives to activate the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel stably expressed in chinese hamster ovary (CHO) cells using the cell-attached patch clamp and iodide efflux techniques. Activation of CFTR channels was obtained with 3-mono, 1,3-di or 1,3,7-tri-substituted alkyl xanthine derivatives (enprofylline, theophylline, aminophylline, IBMX, DPMX and pentoxifylline). By contrast, xanthine derivatives substituted at the C8- or N9-position failed to open CFTR channels. The CFTR chloride channel activity was blocked by glibenclamide (100 μM) but not by DIDS (100 μM). Activation of CFTR by xanthines was not mimicked by the calcium ionophore A23187, adenosine, UTP, ATP or the specific phosphodiesterase inhibitors rolipram, Ro 20-1724 and milrinone. In addition, we found no correlation between the effect of xanthines on CFTR and on the cellular cyclic AMP or ATP levels. We then synthesized a series of 3,7-dimethyl-1-alkyl xanthine derivatives; among them, 3,7-dimethyl-1-propyl xanthine and 3,7-dimethyl-1-isobutyl xanthine both activated CFTR channels without increasing the intracellular cyclic AMP level, while the structurally related 3,7-dimethyl-1-(2-propenyl) xanthine and 3,7-dimethyl-1-(oxiranyl methyl) xanthine were inactive. Our findings delineate a novel function for xanthine compounds and identify the molecular features that enable xanthine activation of CFTR. These results may be useful in the development of new molecules for studying the pharmacology of chloride channels.
ISSN 00071188
Age Range above 22 year
Educational Use Research
Interactivity Type Expositive
Education Level UG and PG
Learning Resource Type Article
Publisher Date 1998-02-01
Journal British Journal of Pharmacology
Volume Number 123
Issue Number 4
Page Count 11
Starting Page 683
Ending Page 693


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Source: PubMed Central