Document Detail

Structure-activity relationship of fenamates as Slo2.1 channel activators.
MedLine Citation:
PMID:  22851714     Owner:  NLM     Status:  MEDLINE    
Niflumic acid, 2-{[3-(trifluoromethyl)phenyl]amino}pyridine-3-carboxylic acid (NFA), a nonsteroidal anti-inflammatory drug that blocks cyclooxygenase (COX), was shown previously to activate [Na(+)](i)-regulated Slo2.1 channels. In this study, we report that other fenamates, including flufenamic acid, mefenamic acid, tolfenamic acid, meclofenamic acid, and a phenyl acetic acid derivative, diclofenac, also are low-potency (EC(50) = 80 μM to 2.1 mM), partial agonists of human Slo2.1 channels heterologously expressed in Xenopus oocytes. Substituent analysis determined that N-phenylanthranilic acid was the minimal pharmacophore for fenamate activation of Slo2.1 channels. The effects of fenamates were biphasic, with an initial rapid activation phase followed by a slow phase of current inhibition. Ibuprofen, a structurally dissimilar COX inhibitor, did not activate Slo2.1. Preincubation of oocytes with ibuprofen did not significantly alter the effects of NFA, suggesting that neither channel activation nor inhibition is associated with COX activity. A point mutation (A278R) in the pore-lining S6 segment of Slo2.1 increased the sensitivity to activation and reduced the inhibition induced by NFA. Together, our results suggest that fenamates bind to two sites on Slo2.1 channels: an extracellular accessible site to activate and a cytoplasmic accessible site in the pore to inhibit currents.
Priyanka Garg; Michael C Sanguinetti
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-31
Journal Detail:
Title:  Molecular pharmacology     Volume:  82     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-22     Completed Date:  2013-02-12     Revised Date:  2013-11-06    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  795-802     Citation Subset:  IM    
Nora Eccles Harrison Cardiovascular Research and Training Institute, Department of Physiology, University of Utah, Salt Lake City, Utah 84112, USA.
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MeSH Terms
Cyclooxygenase Inhibitors / pharmacology
Fenamates / chemistry,  pharmacology*
Ibuprofen / pharmacology
Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / agonists
Niflumic Acid / pharmacology
Oocytes / drug effects,  physiology
Patch-Clamp Techniques
Point Mutation
Potassium Channel Blockers / pharmacology
Potassium Channels / agonists*,  genetics
Structure-Activity Relationship
Xenopus laevis
ortho-Aminobenzoates / pharmacology
Grant Support
Reg. No./Substance:
0/Cyclooxygenase Inhibitors; 0/Fenamates; 0/KCNMA1 protein, human; 0/KCNT2 protein, human; 0/Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; 0/Potassium Channel Blockers; 0/Potassium Channels; 0/ortho-Aminobenzoates; 15687-27-1/Ibuprofen; 4394-00-7/Niflumic Acid; 91-40-7/fenamic acid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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