Indanylidenes. 1. Design and Synthesis of (<i>E</i>)-2-(4,6-Difluoro-1-indanylidene)acetamide, a Potent, Centrally Acting Muscle Relaxant with Antiinflammatory and Analgesic Activity

Musso, David L.; Cochran, Felicia R.; Kelley, James L.; McLean, Ed W.; Selph, Jeffrey L.; Rigdon, Greg C.; Orr, G F; Davis, Roderick; Cooper, Barrett R.; Styles, Virgil L.; Thompson, James B.; Hall, William R.

doi:10.1021/jm020067s

Cited by 59 publications

(52 citation statements)

References 17 publications

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“…For instance, decreased neuronal excitability may be expected after application of the SK channel openers 1-ethyl-2-benzimidazolinone (1-EBIO) [4] and chlorzoxazone [10,89], the SK and IK opener (E)-2-(4,6-difluoro-1-indanylidene) acetamide [65,66], or the selective BK opener benzimidazolone NS1619 [102].…”

Section: Discussionmentioning

confidence: 99%

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

Sarantopoulos¹,

McCallum²,

Rigaud³

et al. 2007

Brain Research

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Calcium-activated potassium channels regulate AHP and excitability in neurons. Since we have previously shown that axotomy decreases I Ca in DRG neurons, we investigated the association between I Ca and K (Ca) currents in control medium-sized (30-39 μM) neurons, as well as axotomized L5 or adjacent L4 DRG neurons from hyperalgesic rats following L5 SNL. Currents in response to AP waveform voltage commands were recorded first in Tyrode's solution and sequentially after: 1) blocking Na + current with NMDG and TTX; 2) addition of K (Ca) blockers with a combination of apamin 1μM, iberiotoxin 200 nM, and clotrimazole 500 nM; 3) blocking remaining K + current with the addition of 4-AP, TEA-Cl, and glibenclamide; and 4) blocking I Ca with cadmium. In separate experiments, currents were evoked (HP −60 mV, 200 ms square command pulses from −100 to +50 mV) while ensuring high levels of activation of I K(Ca) by clamping cytosolic Ca 2+ concentration with pipette solution in which Ca 2+ was buffered to1μM. This revealed I K(Ca) with components sensitive to apamin, clotrimazole and iberiotoxin. SNL decreases total I K(Ca) in axotomized (L5) neurons, but increases total I K(Ca) in adjacent (L4) DRG neurons. All I K(Ca) subtypes are decreased by axotomy, but iberiotoxin-sensitive and clotrimazole-sensitive current densities are increased in adjacent L4 neurons after SNL. In an additional set of experiments we found that small sized control DRG neurons also expressed iberiotoxin-sensitive currents, which are reduced in both axotomized (L5) and adjacent (L4) neurons.Conclusions: Axotomy decreases I K(Ca) due to a direct effect on K (Ca) channels. Axotomy-induced loss of I Ca may further potentiate current reduction. This reduction in I K(Ca) may contribute to elevated excitability after axotomy. Adjacent neurons (L4 after SNL) exhibit increased I K(Ca) current.

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Section: Discussionmentioning

confidence: 99%

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

Sarantopoulos¹,

McCallum²,

Rigaud³

et al. 2007

Brain Research

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“…( 4)), which also distantly resembles EBIO, activates KCa3.1 with an EC 50 of 5 µM and claims a wide range of bicyclic esters and amides as KCa2 and KCa3.1 channel openers [255]. Interestingly, GW275919X ((E)-2-(2,4-difluoro-1-indanylidene)acetamide) had been previously patented and published as a central muscle relaxant that does not produce sedation and has been taken into phase-1 clinical trials for back pain [256]. Although GW275919X probably has other activities, it is very likely that KCa2 channel activation is at least partially responsible for its effects.…”

Section: Kca2 and Kca31 Channel Activatorsmentioning

confidence: 99%

Modulators of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels and their Therapeutic Indications

Wulff

Kolski-Andreaco

Sankaranarayanan

et al. 2007

CMC

200

243

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Calcium-activated potassium channels modulate calcium signaling cascades and membrane potential in both excitable and non-excitable cells. In this article we will review the physiological properties, the structure activity relationships of the existing peptide and small molecule modulators and the therapeutic importance of the three small-conductance channels KCa2.1-KCa2.3 (a.k.a. SK1-SK3) and the intermediate-conductance channel KCa3.1 (a.k.a. IKCa1). The apamin-sensitive KCa2 channels contribute to the medium afterhyperpolarization and are crucial regulators of neuronal excitability. Based on behavioral studies with apamin and on observations made in several transgenic mouse models, KCa2 channels have been proposed as targets for the treatment of ataxia, epilepsy, memory disorders and possibly schizophrenia and Parkinson's disease. In contrast, KCa3.1 channels are found in lymphocytes, erythrocytes, fibroblasts, proliferating vascular smooth muscle cells, vascular endothelium and intestinal and airway epithelia and are therefore regarded as targets for various diseases involving these tissues. Since two classes of potent and selective small molecule KCa3.1 blocker, triarylmethanes and cyclohexadienes, have been identified, several of these postulates have already been validated in animal models. The triarylmethane ICA-17043 is currently in phase III clinical trials for sickle cell anemia while another triarylmethane, TRAM-34, has been shown to prevent vascular restenosis in rats and experimental autoimmune encephalomyelitis in mice. Experiments showing that a cyclohexadiene KCa3.1 blocker reduces infarct volume in a rat subdural hematoma model further suggest KCa3.1 as a target for the treatment of traumatic and possibly ischemic brain injury. Taken together KCa2 and KCa3.1 channels constitute attractive new targets for several diseases that currently have no effective therapies.

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“…2(B) shows the 1 H NMR spectrum of WSPCS. The characteristic peaks of phosphonium groups are the peak of the methylene hydrogen (-CO-CH 2 *-CH 2 -P-) at 2.70 ppm [31] and the absorption bands between 7.68 and 8.02 ppm due to the hydrogen of benzene rings of triphenylphosphonium groups [32]. In Fig.…”

Section: Ft-ir Analysismentioning

confidence: 96%

Novel water soluble phosphonium chitosan derivatives: Synthesis, characterization and cytotoxicity studies

Wang

Guo

et al. 2011

International Journal of Biological Macromolecules

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Indanylidenes. 1. Design and Synthesis of (E)-2-(4,6-Difluoro-1-indanylidene)acetamide, a Potent, Centrally Acting Muscle Relaxant with Antiinflammatory and Analgesic Activity

Cited by 59 publications

References 17 publications

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

Opposing effects of spinal nerve ligation on calcium-activated potassium currents in axotomized and adjacent mammalian primary afferent neurons

Modulators of Small- and Intermediate-Conductance Calcium-Activated Potassium Channels and their Therapeutic Indications

Novel water soluble phosphonium chitosan derivatives: Synthesis, characterization and cytotoxicity studies

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