Analogs of a potent maxi-K potassium channel opener with an improved inhibitory profile toward cytochrome P450 isozymes

Vrudhula, Vivekananda M.; Dasgupta, Bireshwar; Boissard, Christopher G.; Gribkoff, Valentin K.; Santone, Kenneth S.; Dalterio, R. A.; Lodge, Nicholas J.; Starrett, John E.

doi:10.1016/j.bmcl.2005.06.056

Cited by 9 publications

(5 citation statements)

References 12 publications

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“…Recently quinolinone 3 was also shown to decrease stress-induced colonic motility and visceral nociception in rats, indicating potential utility in mitigating irritable bowel syndrome . In an effort to further identify novel maxi-K channel openers belonging to this class, modifications done on ring B at positions 1 and 3 also led to several derivatives with significant maxi-K channel opening ability. , Both 3 and its N -methyl derivative 4 turned out to be potent leads with significant maxi-K channel opening ability. ,,, With this series of compounds, the presence of an underivatized phenolic hydroxyl group on ring C was also identified as a general requirement for activity. In order to further understand the maxi-K channel opening ability of this class of compounds, modifications in the vicinity of the phenolic hydroxyl group in the C ring were undertaken.…”

Section: Introductionmentioning

confidence: 96%

“…11 In an effort to further identify novel maxi-K channel openers belonging to this class, modifications done on ring B at positions 1 and 3 also led to several derivatives with significant maxi-K channel opening ability. 12,13 Both 3 and its N-methyl derivative 4 turned out to be potent leads with significant maxi-K channel opening ability. 9,10,12,13 With this series of compounds, the presence of an underivatized phenolic hydroxyl group on ring C was also identified as a general requirement for activity.…”

Section: Introductionmentioning

confidence: 99%

“…12,13 Both 3 and its N-methyl derivative 4 turned out to be potent leads with significant maxi-K channel opening ability. 9,10,12,13 With this series of compounds, the presence of an underivatized phenolic hydroxyl group on ring C was also identified as a general requirement for activity. In order to further understand the maxi-K channel opening ability of this class of compounds, modifications in the vicinity of the phenolic hydroxyl group in the C ring were undertaken.…”

Section: Introductionmentioning

confidence: 99%

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Atropisomeric 3-(β-hydroxyethyl)-4-arylquinolin-2-ones as Maxi-K Potassium Channel Openers

et al. 2007

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The synthesis of a series of 3-beta-hydroxyethyl-4-arylquinolin-2-ones is described. These compounds contain hydrophilic and hydrophobic substituents ortho to the phenolic OH in the C ring of the quinolinone. Electrophysiological evaluation of the panel of compounds revealed that 11 and 16 with an unbranched ortho substituent retain activity as maxi-K ion channel openers. Members of this series of compounds can exist as stable atropisomers. Calculated estimates of the energy barrier for rotation around the aryl-aryl single bond in 3 is 31 kcal/mol. The atropisomers of (+/-)-3, (+/-)-4, and (+/-)-11 were separated by chiral HPLC and tested for their effect on maxi-K mediated outward current in hSlo injected X. laevis oocytes. The (-) isomer in each case was found to be more active than the corresponding (+) isomer, suggesting that the ion channel exhibits stereoselective activation. X-ray crystallographic structures of (+)-3 and (+)-11 were determined. Evaluation of the stability of (-)-3 at 80 degrees C in n-butanol indicated a 19.6% conversion to (+)-3 over 72 h. In human serum at 37 degrees C (-)-3 did not racemize over the course of the 30 h study.

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Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Atropisomeric 3-(β-hydroxyethyl)-4-arylquinolin-2-ones as Maxi-K Potassium Channel Openers

et al. 2007

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“…Because of its role in preventing excessive Ca 2+ buildup and abnormal glutamate release, BK channels have become an attractive pharmacological target for developing neuroprotective agents (Vrudhula et al, 2005;Wu, 2003). Indeed, numerous BK channel openers are currently under investigation to ameliorate ischemic damage and trauma (Cheney et al, 2001;Gribkoff et al, 2001b;Hewawasam et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

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In the hippocampus, BK channels are preferentially localized in presynaptic glutamatergic terminals including mossy fibers where they are thought to play an important role regulating excessive glutamate release during hyperactive states. Large conductance calcium-activated potassium channels (BK, MaxiK, Slo) have recently been implicated in the pathogenesis of genetic epilepsy. However, the role of BK channels in acquired mesial temporal lobe epilepsy (MTLE) remains unknown. Here we used immunohistochemistry, laser scanning confocal microscopy (LSCM), western immunoblotting and RT-PCR to investigate the expression pattern of the alpha-pore forming subunit of BK channels in the hippocampus and cortex of chronically epileptic rats obtained by the pilocarpine model of MTLE. All epileptic rats experiencing recurrent spontaneous seizures exhibited a significant down-regulation of BK channel immunostaining in the mossy fibers at the hilus and stratum lucidum of the CA3 area. Quantitative analysis of immunofluorescence signals by LSCM revealed a significant 47% reduction in BK channel in epileptic rats when compared to age-matched non-epileptic control rats. These data correlate with a similar reduction in BK channel protein levels and transcripts in the cortex and hippocampus. Our data indicate a seizure-related down-regulation of BK channels in chronically epileptic rats. Further functional assays are necessary to determine whether altered BK channel expression is an acquired channelopathy or a compensatory mechanism affecting the network excitability in MTLE. Moreover, seizure-mediated BK down-regulation may disturb neuronal excitability and presynaptic control at glutamatergic terminals triggering exaggerated glutamate release and seizures.

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“…Nevertheless, it has been also reported elsewhere that such a compound inhibits the cytochrome P450 (CYP) 2C9 isoform with an IC 50 of 1.7 µM. In an effort to decrease such an inhibitory profile, while preserving the BK channel activity, a successful synthetic study has been recently carried out [69].…”

Section: Bk Channel Openersmentioning

confidence: 97%

Potassium Channel Openers: The Case of BK Channel Activators

Nardi¹,

Calderone²,

Olesen

2006

LDDD

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Large-conductance calcium-activated potassium channels, also known as BK or Maxi-K channels, occur in many types of cells, where they play an essential role in the regulation of cell excitability and function. BK channel openers constitute a heterogeneous group of organic compounds being able to activate BK channels and having a wide therapeutic potential for the treatment of different neurological, urological and cardiovascular diseases. This review addresses the novel research on BK channels as drug targets as well as it reports recent developments in the chemistry of BK channel openers and in the chemical structural aspects determining their activity.

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Analogs of a potent maxi-K potassium channel opener with an improved inhibitory profile toward cytochrome P450 isozymes

Cited by 9 publications

References 12 publications

Atropisomeric 3-(β-hydroxyethyl)-4-arylquinolin-2-ones as Maxi-K Potassium Channel Openers

Atropisomeric 3-(β-hydroxyethyl)-4-arylquinolin-2-ones as Maxi-K Potassium Channel Openers

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Potassium Channel Openers: The Case of BK Channel Activators

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