Anticonvulsant activities of some arylsemicarbazones displaying potent oral activity in the maximal electroshock screen in rats accompanied by high protection indices

Dimmock, J. R.; Sidhu, K. K.; Thayer, RS; Mack, Philip C.; Duffy, Michael J.; Reid, R. S.; Quail, J. Wilson; Pugazhenthi, U.; Ong, A. S. H.

doi:10.1021/jm00068a001

Cited by 59 publications

(34 citation statements)

References 7 publications

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“…In 1993 and 1996, Dimmock et al (1993;1996) reported on (aryloxy)aryl semicarbazones as compounds with potent anticonvulsant activity in maximum electroshock-and pentylenetetrazole-induced seizure models in rodents. These compounds did not have obvious structural similarities with classical anticonvulsants, and their mechanism of action was not known.…”

Section: Introductionmentioning

confidence: 99%

“…These compounds did not have obvious structural similarities with classical anticonvulsants, and their mechanism of action was not known. Initial binding experiments suggested interactions with g-aminobutyric acid (GABA)-gated Cl À channels (Dimmock et al, 1993). However, these effects were only seen at high concentrations, and subsequent experiments revealed no positive modulation of native or recombinant GABA A channels expressed in Xenopus oocytes (E.R.…”

Section: Introductionmentioning

confidence: 99%

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V102862 (Co 102862): a potent, broad‐spectrum state‐dependent blocker of mammalian voltage‐gated sodium channels

Ilyin

Hodges

Whittemore

et al. 2005

British J Pharmacology

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4‐(4‐Fluorophenoxy)benzaldehyde semicarbazone (V102862) was initially described as an orally active anticonvulsant with robust activity in a variety of rodent models of epilepsy. The mechanism of action was not known. We used whole‐cell patch‐clamp techniques to study the effects of V102862 on native and recombinant mammalian voltage‐gated Na+ channels. V102862 blocked Na+ currents (INa) in acutely dissociated cultured rat hippocampal neurons. Potency increased with membrane depolarization, suggesting a state‐dependent mechanism of inhibition. There was no significant effect on the voltage dependence of activation of INa. The dissociation constant for the inactivated state (KI) was ∼0.6 μM, whereas the dissociation constant for the resting state (KR) was >15 μM. The binding to inactivated channels was slow, requiring a few seconds to reach steady state at −80 mV. The mechanism of inhibition was characterized in more detail using human embryonic kidney‐293 cells stably expressing rat brain type IIA Na+ (rNav1.2) channels, a major Na+ channel α subunit in rat hippocampal neurons. Similar to hippocampal neurons, V102862 was a potent state‐dependent blocker of rNav1.2 channels with a KI of ∼0.4 μM and KR ∼30 μM. V102862 binding to inactivated channels was relatively slow (k+≃1.7 μM−1 s−1). V102862 shifted the steady‐state availability curve in the hyperpolarizing direction and significantly retarded recovery of Na+ channels from inactivation. These results suggest that inhibition of voltage‐gated Na+ channels is a major mechanism underlying the anticonvulsant properties of V102862. Moreover, understanding the biophysics of the interaction may prove to be useful in designing a new generation of potent Na+ channel blocker therapeutics. British Journal of Pharmacology (2005) 144, 801–812. doi:10.1038/sj.bjp.0706058

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

V102862 (Co 102862): a potent, broad‐spectrum state‐dependent blocker of mammalian voltage‐gated sodium channels

Ilyin

Hodges

Whittemore

et al. 2005

British J Pharmacology

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“…A few compounds (50) with p-nitrophenyl substitution also showed activity in ScSTY tests. Acetophenone semicarbazone (73) and phenyl acetaldehyde semicarbazone (73) protected against seizures induced by ScPTZ (ED 50 60.75 mg kg -1 ) and subcutaneous bicuculline (ScBIC) (ED 50 57.63 mg kg -1 ) (Fig. 14).…”

Section: Mechanism Of Action Of Semicarbazone Anticonvulsantsmentioning

confidence: 97%

Semicarbazone – a versatile therapeutic pharmacophore for fragment based anticonvulsant drug design

Pandeya¹

2012

Acta Pharmaceutica

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During the last fifteen years, semicarbazones have been extensively investigated for their anticonvulsant properties. 4-(4-Flurophenoxy) benzaldehyde semicarbazone (C0102862, V102862) was discovered as a lead molecule and is being developed as a potent antiepileptic drug, with maximal electroshock (MES) ED50 of i.p. 12.9 mg kg-1. In MES (oral screen), this compound has a protective index (PI = TD50/ED50 > 315) higher than carbamazepine (PI 101), phenytoin (PI > 21.6) and valproate (PI 2.17). The compound is a potent sodium channel blocker. Other semicarbazones have demonstrated activity in various chemoshock screens, like subcutaneous pentylenetetrazole, subcutaneous strychnine, subcutaneous picrotoxin and subcutaneous bicculine. Semicarbazones are also GABA-transaminase inhibitors. Extensive structure- -activity relationship has demonstrated that F, Cl, Br and NO2 substituents in the arylhydrophobic pocket and a hydrogen bonding domain (HBD) are generally found in active anticonvulsant agents.

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“…[24][25][26]33,38) It was suggested that (thio)semicarbazones anticonvulsant activity is mediated through GABA-mediated mechanism. 19,22,29,32,37,41) In the present investigation the two anticonvulsant candidates, chromones or flavones and thiosemicarbazones, were amalgamated to obtain more potent anticonvulsants compounds of series 1 and 2. In the synthesized hybrid compounds the chromone or the furochromone ring acts as the hydrophobic aryl ring required for binding which itself possesses anticonvulsant tendency.…”

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confidence: 99%

Synthesis and Anticonvulsant Activity of Certain Substituted Furochromone, Benzofuran and Flavone Derivatives

et al. 2010

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Despite the optimal use of the currently available antiepileptic drugs, 30 to 40% of the epileptic population fails to experience seizure control, and others do so only at the expense of significant toxic effects that range in severity from minimal brain impairment to death from aplastic anemia or hepatic failure.1-3) These facts provoked the need for new anticonvulsant drugs with higher potency and fewer side effects. Several studies reported that chromone derivatives are promising anticonvulsant candidates that perform their activity through a g-aminobutyric acid (GABA)-mediated mechanism. [4][5][6][7][8][9][10][11][12][13][14][15][16][17] Likewise, flavones (2-phenylbenzopyrons) are with a well known positive GABA-modulating ability; their central activity was attributed to their potential to penetrate the blood-brain barrier which is strongly correlated to their lipophilicity.18) Semicarbazones and their bioisosteres thiosemicarbazones, have a documented essential role in the design of novel anticonvulsant agents that performing their anticonvulsant activity also through a GABA-mediated mechanism.19-41) Extensive structure-activity relationship studies proposed certain pharmacophoric requirements for (thio)-semicarbazones interaction at the binding site which are a hydrophobic binding area represented by aryl or heteroaryl group and a hydrogen bonding domain represented by the NH-CO(S)-NH system. [24][25][26]33,38) It was suggested that (thio)semicarbazones anticonvulsant activity is mediated through GABA-mediated mechanism. 19,22,29,32,37,41) In the present investigation the two anticonvulsant candidates, chromones or flavones and thiosemicarbazones, were amalgamated to obtain more potent anticonvulsants compounds of series 1 and 2. In the synthesized hybrid compounds the chromone or the furochromone ring acts as the hydrophobic aryl ring required for binding which itself possesses anticonvulsant tendency. On the other hand, various bicyclic heterocycles containing thiosemicarbazono group showed significant anticonvulsant activity. 33,34,[42][43][44] Herein the tricyclic furochromone moiety was simplified to the bicyclic benzofuran system, which was reported to possess anticonvulsant activity [42][43][44] to give compounds of series 3. Obviously, the compounds of this series are the bicyclic analogs of the reported phenyl congener 4 synthesized by Dimmock et al. which showed marked anticonvulsant activity. 20) Replacement of the phenyl ring in 4 by the bicyclic benzofuran structure is thought to increase the hydrophobic aryl area which binds to the binding site and thus may enhance the binding. Moreover, the effect of the hydrophobic group on the terminal amino group of the thiosemicarbazono moiety was studied in the synthesized compounds of series 1, 2 and 3.Due to certain limitations associated with the (thio)semicarbazone functionality, mainly the poor solubility and liability to metabolism 45) ; improvement of the molecule, pharmacologically and pharmaceutically, was carried out by replacement of the th...

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Anticonvulsant activities of some arylsemicarbazones displaying potent oral activity in the maximal electroshock screen in rats accompanied by high protection indices

Cited by 59 publications

References 7 publications

V102862 (Co 102862): a potent, broad‐spectrum state‐dependent blocker of mammalian voltage‐gated sodium channels

V102862 (Co 102862): a potent, broad‐spectrum state‐dependent blocker of mammalian voltage‐gated sodium channels

Semicarbazone – a versatile therapeutic pharmacophore for fragment based anticonvulsant drug design

Synthesis and Anticonvulsant Activity of Certain Substituted Furochromone, Benzofuran and Flavone Derivatives

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