Positive allosteric modulation of GABAA receptors by a novel antiepileptic drug cenobamate

Sharma, Ramesh; Nakamura, Michiko; Neupane, Chiranjivi; Jeon, Byeong Hwa; Shin, Hye‐Won; Melnick, Susan M.; Glenn, Kelli; Jang, Il‐Sung; Park, Jin Bong

doi:10.1016/j.ejphar.2020.173117

Cited by 77 publications

(81 citation statements)

References 38 publications

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“…7 Similar studies also suggest that CBM acts as a positive allosteric modulator (PAM) of both synaptic and extrasynaptic GABA A receptors at a site independent of the BZD binding site. 8 These data provide compelling insight into the novel MOAs of CBM; however, these are the only studies we are aware of that have thoroughly investigated CBM's molecular mechanisms. Because this has not been largely addressed in the literature, we sought to provide insight into CBM's novel MOAs by comparing its unique preclinical profile to other ASMs with similar MOAs.…”

Section: Action Of Cbmmentioning

confidence: 99%

“…The precise mechanism(s) through which CBM exerts its broadspectrum antiseizure effects is not known, but experimental evidence suggests it may have dual MOAs on voltage-gated | 2335 sodium currents and GABA A receptors. 7,8 Specifically, mechanistic studies in acutely isolated hippocampal CA3 neurons demonstrate that CBM can reduce repetitive neuronal firing by preferentially inhibiting the noninactivating portion of sodium currents, also known as I NaP . 7 Similar studies also suggest that CBM acts as a positive allosteric modulator (PAM) of both synaptic and extrasynaptic GABA A receptors at a site independent of the BZD binding site.…”

Section: Action Of Cbmmentioning

confidence: 99%

“…This suggests that BARBs can modulate the function of extrasynaptic GABA A receptors responsible for I tonic inhibition. 19 Given that part of CBM's activity may be attributed to its action at a site independent of the BZD binding site on GABA A receptors and its ability to enhance tonic GABAergic inhibition, 8 it stands to reason that its antiseizure profile would be more similar to BARBs, such as PB. CBM shared a profile similar to that of PB in that at doses that did not cause behavioral impairment, they were both effective against generalized seizures induced by MES stimulation, PTZ and PIC.…”

Section: Gaba a Receptorsmentioning

confidence: 99%

“…7 In addition, CBM has been reported to enhance γ-aminobutyric acid (GABA)-mediated inhibition by positive allosteric modulation of the GABA A receptor through an effect at a nonbenzodiazepine (BZD)-sensitive binding site. 8 Experimental evidence also suggests CBM may target both synaptic and extrasynaptic GABA A receptors, as witnessed by its effects on both phasic (I phasic ) and tonic (I tonic ) GABA A currents. These dual activities of CBM at VGSCs and GABA A receptors (Table 1) may help to explain its broad preclinical activity and support its clinical efficacy in patients with difficult-to-control focal epilepsy.…”

Section: Introductionmentioning

confidence: 99%

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Cenobamate (XCOPRI): Can preclinical and clinical evidence provide insight into its mechanism of action?

2020

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Approximately one-third of people living with epilepsy are unable to obtain seizure control with the currently marketed antiseizure medications (ASMs), creating a need for novel therapeutics with new mechanisms of action. Cenobamate (CBM) is a tetrazole alkyl carbamate derivative that received US Food and Drug Administration approval in 2019 for the treatment of adult partial onset (focal) seizures. Although CBM displayed impressive seizure reduction in clinical trials across all seizure types, including focal aware motor, focal impaired awareness, and focal to bilateral tonicclonic seizures, the precise mechanism(s) through which CBM exerts its broad-spectrum antiseizure effects is not known. Experimental evidence suggests that CBM differentiates itself from other ASMs in that it appears to possess dual modes of action (MOAs); that is, it predominately blocks persistent sodium currents and increases both phasic and tonic γ-aminobutyric acid (GABA) inhibition. In this review, we analyze the preclinical efficacy of CBM alongside ASMs with similar MOAs to better understand the mechanism(s) through which CBM achieves such broad-spectrum seizure protection. CBM's preclinical performance in tests, including the mouse 6-Hz model of treatment-resistant seizures, the chemoconvulsant seizure models of generalized epilepsy, and the rat hippocampal kindling model of focal epilepsy, was distinct from other voltage-gated sodium channel blockers and GABA A modulators. This distinction, in light of its proposed mechanism(s) of action, provides insight into the impressive clinical efficacy of CBM in the adult patient with focal onset epilepsy. The results of this comparative reverse translational analysis suggest that CBM is a mechanistically distinct ASM that offers an important advancement in drug development for treatment of therapy-resistant epilepsy.

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Section: Action Of Cbmmentioning

confidence: 99%

Section: Action Of Cbmmentioning

confidence: 99%

Section: Gaba a Receptorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cenobamate (XCOPRI): Can preclinical and clinical evidence provide insight into its mechanism of action?

2020

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“…Cenobamate has been shown to reduce neuronal excitability by enhancing the fast and slow inactivation of sodium channels and preferentially inhibiting the persistent component of the sodium channel current [12]. Moreover, cenobamate acts as a positive allosteric modulator of high affinity GABA A receptors, binding at a non-benzodiazepine site [13].…”

Section: Introductionmentioning

confidence: 99%

Adjunctive Cenobamate for Focal-Onset Seizures in Adults: A Systematic Review and Meta-Analysis

et al. 2020

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Background Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. This drug can enhance the inactivated state of voltage-gated sodium channels, preferentially inhibiting the persistent component of the sodium channel current, and acts as a positive allosteric modulator of GABA A receptors, binding at a non-benzodiazepine site. Objective We assessed the efficacy and safety of adjunctive cenobamate for the treatment of focal-onset seizures in adult patients with epilepsy using meta-analytical techniques. Methods We systematically searched (May, week 4, 2020) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry (http://www.clini caltr ials.gov). There were no date limitations or language restrictions. Randomized, placebo-controlled, single or doubleblinded, add-on trials of cenobamate in adult patients with uncontrolled focal-onset seizures were identified. Main outcomes included the proportion of patients with ≥ 50 and 100% reduction in seizure frequency during the maintenance treatment period compared with baseline and the incidence of treatment withdrawal and adverse events (AEs). Risk ratio (RR) with 95% confidence interval (CI) was estimated for each outcome. Results Two trials were included, overall enrolling 659 patients (442 for the add-on cenobamate group and 217 for the add-on placebo group). Seizure frequency reduction by at least 50% occurred during the maintenance phase in 50.1% of the patients randomized to cenobamate and 23.5% of the placebo-treated participants (RR 2.18, 95% CI 1.67-2.85; p < 0.001). The pooled estimated RR to achieve seizure freedom for the cenobamate group in comparison with placebo was 3.71 (95% CI 1.93-7.14; p < 0.001). Withdrawal from randomized treatment occurred in 16.7 and 11.1% of participants receiving cenobamate and placebo, respectively (RR 1.34, 95% CI 0.85-2.09; p = 0.205). Treatment was discontinued due to AEs in 12.2 and 4.1% of the patients in the active and control arms (RR 2.27, 95% CI 1.08-4.79; p = 0.031). AEs were reported in 76.9 and 66.8% of the patients during treatment with cenobamate and placebo (RR 1.14, 95% CI 1.02-1.26; p = 0.021). The cenobamate-associated AEs included somnolence, dizziness, fatigue, balance disorder, and diplopia. Conclusions Adjunctive cenobamate in adult patients with uncontrolled focal-onset seizures is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

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A Phase 1 Clinical Study Evaluating the Effects of Cenobamate on the QT Interval

Darpö

Sager

Xue

et al. 2022

Clinical Pharm in Drug Dev

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Cenobamate is an antiseizure medication for uncontrolled focal seizures. This thorough QT study assessed the effects of therapeutic and supratherapeutic cenobamate doses (maximum recommended dose, 400 mg/day) on correct QT interval (QTc) in healthy adults (N = 108) randomly assigned to 1 of 3 treatments: (A) cenobamate (days 1-63) up-titrated by 50-mg increments weekly to a 200 mg/day therapeutic dose (day 35) and then by 100 mg weekly to a 500 mg/day supratherapeutic dose (day 63), with placebo-moxifloxacin (days −1 and 64); (B) moxifloxacin 400 mg (day −1; positive control), placebo-cenobamate (days 1-63), and placebo-moxifloxacin (day 64); and (C) placebo-moxifloxacin (day −1), placebo-cenobamate (days 1-64), and moxifloxacin 400 mg (day 64). The primary end point was baselineadjusted, placebo-corrected QTc ( QTcF; corrected for heart rate [HR] by Fridericia's method) with cenobamate 200 and 500 mg/day. Baseline electrocardiographic parameters were balanced across groups. Mean QTcF was negative throughout for cenobamate doses (largest: day 35, −10.8 milliseconds; day 63, −18.4 milliseconds). Based on concentration-QTc analysis, QTcF effect was predicted as −9.85 and −17.14 milliseconds at mean peak plasma levels of therapeutic (200 mg/day; 23.06 μg/mL) and supratherapeutic (500 mg/day; 63.96 μg/mL) doses. Cenobamate had no clinically relevant prolonging effect on electrocardiographic parameters (eg, PR, QRS); HR effects were similar to placebo. Cenobamate showed slight dose-related shortening of QTc, but to a degree not known to be clinically relevant (no reductions ≤340 milliseconds). Cenobamate had no clinically relevant effects on HR or electrocardiographic parameters and no QTc-prolonging effect at therapeutic/supratherapeutic doses. Cenobamate is contraindicated in patients with short-QT syndrome and caution should be used when coadministering with drugs that shorten QT interval.

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Positive allosteric modulation of GABAA receptors by a novel antiepileptic drug cenobamate

Cited by 77 publications

References 38 publications

Cenobamate (XCOPRI): Can preclinical and clinical evidence provide insight into its mechanism of action?

Cenobamate (XCOPRI): Can preclinical and clinical evidence provide insight into its mechanism of action?

Adjunctive Cenobamate for Focal-Onset Seizures in Adults: A Systematic Review and Meta-Analysis

A Phase 1 Clinical Study Evaluating the Effects of Cenobamate on the QT Interval

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