Recent Developments in the Biology and Medicinal Chemistry of Potassium Channel Modulators:  Update from a Decade of Progress

Coghlan, Michael J.; Carroll, William A.; Gopalakrishnan, Murali

doi:10.1021/jm000484+

Cited by 152 publications

(140 citation statements)

References 168 publications

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“…Data analysis. Concentration-response data were fit to the following equation: (1) where I is the current amplitude in the presence of the drug; I max is the current in the absence of drug (for inhibitory responses) or the current in the presence of a saturating drug concentration (for activation responses); [drug] is the concentration of NNC55-0118 or NN414; X is the drug concentration that causes half maximal activation (EC 50 ) or inhibition (IC 50 ), h is the Hill coefficient (slope factor), L is the maximum activation (for activation) or zero (for inhibition). Data were fit using Microcal Origin software.…”

Section: Methodsmentioning

confidence: 99%

“…This leads to membrane depolarisation, activation of voltage-gated Ca 2+ channels, Ca 2+ influx and, in turn, insulin secretion. Activation of the K ATP channel by KCOs hyperpolarizes the pancreatic beta Potassium (K + ) channel openers are a structurally diverse group of compounds which share the common property that they are capable of activating potassium channels [1]. The most clinically important are those cell and suppresses insulin secretion even in the presence of glucose.…”

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confidence: 99%

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Potent and selective activation of the pancreatic beta-cell type K ATP channel by two novel diazoxide analogues

et al. 2003

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Aims/hypothesis. We investigated the pharmacological properties of two novel ATP sensitive potassium (K ATP ) channel openers, 6-Chloro-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NNC 55-0118) and 6-chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (NN414), on the cloned cardiac (Kir6.2/SUR2A), smooth muscle (Kir6.2/SUR2B) and pancreatic beta cell (Kir6.2/ SUR1) types of K ATP channel. Methods. We studied the effects of these compounds on whole-cell currents through cloned K ATP channels expressed in Xenopus oocytes or mammalian cells (HEK293). We also used inside-out macropatches excised from Xenopus oocytes. Results. In HEK 293 cells, NNC 55-0118 and NN414 activated Kir6.2/SUR1 currents with EC 50 values of 0.33 µmol/l and 0.45 µmol/l, respectively, compared with that of 31 µmol/l for diazoxide. Neither compound activated Kir6.2/SUR2A or Kir6.2/SUR2B channels expressed in oocytes, nor did they activate Kir6.2 expressed in the absence of SUR. Current activation was dependent on the presence of intracellular MgATP, but was not supported by MgADP. Conclusion/interpretation. Both NNC 55-0118 and NN414 selectively stimulate the pancreatic beta-cell type of K ATP channel with a higher potency than diazoxide, by interaction with the SUR1 subunit. The high selectivity and efficacy of the compounds could prove useful for treatment of disease states where inhibition of insulin secretion is beneficial. [Diabetologia (2003[Diabetologia ( ) 46:1375[Diabetologia ( -1382

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Potent and selective activation of the pancreatic beta-cell type K ATP channel by two novel diazoxide analogues

et al. 2003

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“…Although channels formed only by four ␣ subunits can be functional, ␤ subunits alter the biophysical and pharmacological properties of homomeric channels, including Ca 2ϩ and voltage sensitivity, and gating kinetics (Valverde et al, 1999;Wallner et al, 1999;Xia et al, 1999;Qian et al, 2002;Ha et al, 2004). Several compounds have been developed and reported to be BK Ca channel openers (e.g., dehydrosoyasaponin-I, maxikdiol, NS-1619, BMS-204352, 17␤-estradiol, ethylbromide tamoxifen, pimaric acid, and epoxyeicosatrienoic acids) (Vergara et al, 1998;Valverde et al, 1999;Coghlan et al, 2001;Dick et al, 2002;Imaizumi et al, 2002). Although some synthetic activators, such as NS-1619 and BMS-204352, act on the ␣ subunit, other openers of BK Ca channels, including dehydrosoyasaponin-I and 17-␤-estradiol, require ␤ subunit for their action (Giangiacomo et al, 1998;Valverde et al, 1999).…”

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confidence: 99%

Electrophysiological Characterization of Benzofuroindole-Induced Potentiation of Large-Conductance Ca²⁺-Activated K⁺Channels

Ha¹,

Lim²,

Lee³

et al. 2005

Mol Pharmacol

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Large-conductance Ca 2ϩ -activated K ϩ (BK Ca ) channels are widely distributed and play key roles in various cell functions. We previously reported the chemical synthesis of several benzofuroindole compounds that act as potent openers of BK Ca channels. In this study, we investigated the mechanism of channel potentiation by one of the compounds, 7-trifluoromethyl-10H-benzo [4,5]furo[3,2-b]indole-1-carboxylic acid (TBIC), using electrophysiological means. This chemical highly activated cloned BK Ca channels from extracellular side independent of ␤ subunits and regardless of the presence of intracellular Ca 2ϩ . The EC 50 and Hill coefficient for rat BK Ca channel ␣ subunit, rSlo, were estimated as 8.9 Ϯ 1.5 M and 0.9, respectively. TBIC shifted the conductance-voltage curve of rSlo channels to more hyperpolarized potentials without altering its voltage dependence. Single-channel recording revealed that TBIC increased the open probability of the channel in a dosedependent manner without any changes in single-channel conductance. Strong potentiation by TBIC was also observed for native BK Ca channels from rat hippocampus pyramidal neurons. Thus, TBIC and the related benzofuroindole compounds can be useful tools to unravel the mechanism of this novel allosteric activation of BK Ca channels.

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“…Erythrocyte dehydration in sickle cell disease can be attributed partly to excessive K ϩ loss through IKCa1 channels that are activated by a rise in intracellular Ca 2ϩ during sickling (10). Clotrimazole and ICA-15451, two potent triarylmethane (TRAM) blockers of this channel, are in clinical trials for the treatment of sickle cell disease (11,12). In intestinal and airway epithelium cells, basolateral expression of the IKCa1 channel modulates apical water and Cl Ϫ secretion (13,14), and blockade of this channel by clotrimazole has been reported to ameliorate secretory diarrhea (15).…”

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confidence: 99%

Delineation of the Clotrimazole/TRAM-34 Binding Site on the Intermediate Conductance Calcium-activated Potassium Channel, IKCa1

Wulff¹,

Gutman²,

Cahalan³

et al. 2001

Journal of Biological Chemistry

137

143

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Recent Developments in the Biology and Medicinal Chemistry of Potassium Channel Modulators: Update from a Decade of Progress

Cited by 152 publications

References 168 publications

Potent and selective activation of the pancreatic beta-cell type K ATP channel by two novel diazoxide analogues

Potent and selective activation of the pancreatic beta-cell type K ATP channel by two novel diazoxide analogues

Electrophysiological Characterization of Benzofuroindole-Induced Potentiation of Large-Conductance Ca²⁺-Activated K⁺Channels

Delineation of the Clotrimazole/TRAM-34 Binding Site on the Intermediate Conductance Calcium-activated Potassium Channel, IKCa1

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Recent Developments in the Biology and Medicinal Chemistry of Potassium Channel Modulators: Update from a Decade of Progress

Cited by 152 publications

References 168 publications

Potent and selective activation of the pancreatic beta-cell type K ATP channel by two novel diazoxide analogues

Potent and selective activation of the pancreatic beta-cell type K ATP channel by two novel diazoxide analogues

Electrophysiological Characterization of Benzofuroindole-Induced Potentiation of Large-Conductance Ca2+-Activated K+Channels

Delineation of the Clotrimazole/TRAM-34 Binding Site on the Intermediate Conductance Calcium-activated Potassium Channel, IKCa1

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Electrophysiological Characterization of Benzofuroindole-Induced Potentiation of Large-Conductance Ca²⁺-Activated K⁺Channels