Blockade of the delayed rectifier potassium current in Drosophila by quinidine and related compounds.
Quinidine is a potent blocker of the delayed rectifier K+ channels (IK). Although it has been used for understanding the physiology of K+ channels in many organisms and for treating cardiac arrhythmia in humans, mechanisms of its interaction with the channel molecule are not well understood. As a first step in understanding these mechanisms, we used the Shaker mutant of Drosophila in which the delayed rectifier can be resolved in complete isolation from other currents and determined the importance of the major groups of quinidine (methoxy, quinoline, quinuclide and the bridge groups) in the blockade of IK. It appears that the quinoline moiety, while possessing little channel-blocking activity by itself, may provide a template for positioning the groups that may be important for affinity and blockade. These groups, in the order of importance in imparting inhibitory activity to quinoline, seemed to be quinuclide > methylene bridge > 6-methoxy group. In particular, the quinoline ring and the quinuclide group, when linked-together by a hydroxymethylene bridge, might be responsible for a major part of the IK blocking activity of quinidine. Action of quinidine was not affected by either quinuclidine, which did not block IK, or by quinoline.
Department of Biochemical Pharmacology, State University of New York at Buffalo 14260, USA.
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Kraliz
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Bhattacharya
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Singh
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects; D018482:Muscle, Skeletal / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000187:drug effects*; D011802:Quinidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D011802:Quinidine; D011188:Potassium