Comparison of Anticonvulsant Potencies of Cyheptamide, Carbamazepine, and Phenytoin

Jones, Gary L.; Amato, Robert J.; Wimbish, Gary H.; Peyton, Gaylon A.

doi:10.1002/jps.2600700611

Cited by 14 publications

(5 citation statements)

References 9 publications

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“…These similarities suggest that antiepileptic acyclic ureas may function in a process analogous to the antiepileptic mechanism ofcyclic ureides, such as phenytoin. Thus it is interesting that the SAR results of this study are in agreement with SAR studies for cyclic ureides by Jones et al (1981) and Codding et a1 (1984).…”

Section: Discussionsupporting

confidence: 91%

A pattern recognition study of acyclic ureide anticonvulsants

Khalil

Weaver

1990

Journal of Pharmacy and Pharmacology

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A pattern recognition structure-activity study employing topological, geometric and physicochemical descriptors was performed on 27 acyclic ureide anticonvulsants. Twelve numerical descriptors were used as variables in a discriminant function analysis which categorized the ureide analogues with respect to their bioactivity. The results from the discriminant function analysis were interpreted to support a model for antiepileptic activity.

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Section: Discussionsupporting

confidence: 91%

A pattern recognition study of acyclic ureide anticonvulsants

Khalil

Weaver

1990

Journal of Pharmacy and Pharmacology

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“…Further supporting a role for positive modulation of Sigma1R in antiseizure activity, the positive allosteric modulator phenytoin has demonstrated antiseizure activity in multiple in vivo epilepsy models, including the MES model [47,51] and a rat model of ischemia-induced epilepsy [48,51]. The antiseizure activity of phenytoin is traditionally attributed to inhibition of voltage-gated sodium channels, but a re-evaluation of the antiseizure mechanism of phenytoin is warranted in light of the recent linkages between Sigma1R and seizures.…”

Section: Positive Modulators Of Sigma1r Have Demonstrated Efficacy Across a Spectrum Of In Vivo Seizure Modelsmentioning

confidence: 99%

“…In addition to the activity of fenfluramine and its major metabolite norfenfluramine at serotonergic receptors, recent preclinical studies in mouse and zebrafish models have identified previously undocumented positive modulatory activity of fenfluramine at sigma-1 receptors (Sigma1Rs) [22,23] (Supplemental Table S2; [4][5][6][22][23][24][25][26][27][28]). This interaction with Sigma1Rs suggests a new mechanism of action for fenfluramine's antiseizure activity (Table 1 [23,25,26,[28][29][30][31][32][33][34][35][36][37][38] and Table 2 [23,[39][40][41][42][43][44][45][46][47][48]). Sigma1Rs have long been associated with seizure-related conditions-from amphetamine-induced seizures to epileptic encephalopathies [49][50][51]-but one of the newer, intriguing possibilities of Sigma1R functionality may involve mediation of non-seizure comorbidities associated with DEE pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

Martin

Reeder

Sourbron

et al. 2021

IJMS

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Developmental and epileptic encephalopathies (DEEs) are complex conditions characterized primarily by seizures associated with neurodevelopmental and motor deficits. Recent evidence supports sigma-1 receptor modulation in both neuroprotection and antiseizure activity, suggesting that sigma-1 receptors may play a role in the pathogenesis of DEEs, and that targeting this receptor has the potential to positively impact both seizures and non-seizure outcomes in these disorders. Recent studies have demonstrated that the antiseizure medication fenfluramine, a serotonin-releasing drug that also acts as a positive modulator of sigma-1 receptors, reduces seizures and improves everyday executive functions (behavior, emotions, cognition) in patients with Dravet syndrome and Lennox-Gastaut syndrome. Here, we review the evidence for sigma-1 activity in reducing seizure frequency and promoting neuroprotection in the context of DEE pathophysiology and clinical presentation, using fenfluramine as a case example. Challenges and opportunities for future research include developing appropriate models for evaluating sigma-1 receptors in these syndromic epileptic conditions with multisystem involvement and complex clinical presentation.

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“…Considering that carbamazepine (CBZ), a commonly used antiepileptic agent, is an iminostilbene derivative with a dibenzazepine nucleus and thus has a tricyclic structure similar to clomipramine ( Figure 1A ) ( Sillanpää et al, 1998 ), and that phenytoin (PHT) (named also 5,5 diphenylhydantoin), another powerful antiepileptic agent, although having a little chemical resemblance, has specific stereochemical features in common with carbamazepine ( Figure 1A ) ( Jones et al, 1981 ), we thought it would have been extremely relevant to investigate the effects of these antiepileptic compounds on GFAP mRNA expression and GFAP folding in an in vitro model of AxD.…”

Section: Introductionmentioning

confidence: 99%

Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander’s Disease

et al. 2021

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Alexander’s disease (AxD) is a rare, usually relentlessly progressive disorder of astroglial cells in the central nervous system related to mutations in the gene encoding the type III intermediate filament protein, glial fibrillary acidic protein (GFAP). The pathophysiology of AxD is only partially understood. Available data indicate that an excessive GFAP gene expression may play a role. In particular, a “threshold hypothesis” has been reported, suggesting that mutant GFAP representing about 20% of the total cellular GFAP should be sufficient to cause disease. Thus, strategies based on reducing cellular mutant GFAP protein levels and/or activating biological processes involved in the correct protein folding could be effective in counteracting the toxic effect of misfolded GFAP. Considering that clomipramine (CLM), which has been selected by a wide small molecules screening as the greatest inhibitory potential drug against GFAP expression, is contraindicated because of its proconvulsant activity in the infantile form of AxD, which is also characterized by the occurrence of epileptic seizures, two powerful antiepileptic agents, carbamazepine (CBZ) and phenytoin (PHT), which share specific stereochemical features in common with CLM, were taken into consideration in a reliable in vitro model of AxD. In the present work, we document for the first time that CBZ and PHT have a definite inhibitory effect on pathological GFAP cellular expression and folding. Moreover, we confirm previous results of a similar beneficial effect of CLM. In addition, we have demonstrated that CBZ and CLM play a refolding effect on mutant GFAP proteins, likely ascribed at the induction of CRYAB expression, resulting in the decrease of mutant GFAP aggregates formation. As CBZ and PHT are currently approved for use in humans, their documented effects on pathological GFAP cellular expression and folding may indicate a potential therapeutic role as disease-modifying agents of these drugs in the clinical management of AxD, particularly in AxD patients with focal epilepsy with and without secondary generalization.

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Comparison of Anticonvulsant Potencies of Cyheptamide, Carbamazepine, and Phenytoin

Cited by 14 publications

References 9 publications

A pattern recognition study of acyclic ureide anticonvulsants

A pattern recognition study of acyclic ureide anticonvulsants

An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

Beneficial Effect of Phenytoin and Carbamazepine on GFAP Gene Expression and Mutant GFAP Folding in a Cellular Model of Alexander’s Disease

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