Structure-Activity Relationship of Fenamates as Slo2.1 Channel Activators

Abstract

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 ϩ ] 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 ϭ 80 M 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.

Influence of the N Terminus on the Biophysical Properties and Pharmacology of TREK1 Potassium Channels

“…Fenamates also both activate and inhibit the Na-dependent Slo2.1 (K Ca 4.2) channels through binding to distinct sites on the channel (Garg and Sanguinetti, 2012). In these channels, MFA and diclofenac were more potent activators than FFA and NFA.…”

International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium-Activated and Sodium-Activated Potassium Channels

“…They are inhibited by quinidine, clofilium, and isoflurane (Bhattacharjee et al, 2003; Berg et al, 2007; Kaczmarek et al de Los Angeles Tejada et al, 2012b). They are strongly activated by niflumic acid and other fenamates, although with low potency (Dai et al, 2010;Garg and Sanguinetti, 2012). These agents uncouple the channels from modulation by either Na + or transmembrane voltage and greatly increase current even in the absence of internal Na + ions.…”

“…These agents uncouple the channels from modulation by either Na + or transmembrane voltage and greatly increase current even in the absence of internal Na + ions. The action of fenamates, which is nonspecific in that they also affect many other channels including K Ca 1.1 (Gribkoff et al, 1996), is biphasic, suggesting they bind to two distinct sites within K Na 1.2 (Garg and Sanguinetti, 2012).…”

Administration of the nonsteroidal anti-inflammatory drug tolfenamic acid at embryo transfer improves maintenance of pregnancy and embryo survival in recipient mice

“…Tolfenamic acid not only inhibits COX but also 5-1ipoxygenase, both enzymes are involved in the pathways of arachidonic acid metabolism [18,19]. Fenamates are also low-potency modulators of a diversity of ion channels and enzymes, exhibiting either activator or inhibitory effects [20]. The use of tolfenamic acid in recipient females at embryo transfer to improve the maintenance of the pregnancy has not been proposed in any specie.…”