Synthesis and Evaluation of Potent KCNQ2/3-Specific Channel Activators

Kumar, Mukesh; Reed, Nicholas L.; Liu, Ruiting; Aizenman, Elias; Wipf, Peter; Tzounopoulos, Thanos

doi:10.1124/mol.115.103200

Cited by 56 publications

(46 citation statements)

References 48 publications

(58 reference statements)

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“…KCNQ2 is a voltage-gated non-inactivating potassium ion channel that is downregulated in the epileptic human hippocampus (60,61). Drugs activating these channels reduce neuronal excitability and have antiepileptic efficacy (62). Retigabine, a positive allosteric modulator of KCNQ2 , has recently been licenced for the treatment of epilepsy (63).…”

Section: Resultsmentioning

confidence: 99%

Genetic regulation of gene expression in the epileptic human hippocampus

Mirza

Appleton

Burn

et al. 2017

Human Molecular Genetics

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Epilepsy is a serious and common neurological disorder. Expression quantitative loci (eQTL) analysis is a vital aid for the identification and interpretation of disease-risk loci. Many eQTLs operate in a tissue- and condition-specific manner. We have performed the first genome-wide cis-eQTL analysis of human hippocampal tissue to include not only normal (n = 22) but also epileptic (n = 22) samples. We demonstrate that disease-associated variants from an epilepsy GWAS meta-analysis and a febrile seizures (FS) GWAS are significantly more enriched with epilepsy-eQTLs than with normal hippocampal eQTLs from two larger independent published studies. In contrast, GWAS meta-analyses of two other brain diseases associated with hippocampal pathology (Alzheimer’s disease and schizophrenia) are more enriched with normal hippocampal eQTLs than with epilepsy-eQTLs. These observations suggest that an eQTL analysis that includes disease-affected brain tissue is advantageous for detecting additional risk SNPs for the afflicting and closely related disorders, but not for distinct diseases affecting the same brain regions. We also show that epilepsy eQTLs are enriched within epilepsy-causing genes: an epilepsy cis-gene is significantly more likely to be a causal gene for a Mendelian epilepsy syndrome than to be a causal gene for another Mendelian disorder. Epilepsy cis-genes, compared to normal hippocampal cis-genes, are more enriched within epilepsy-causing genes. Hence, we utilize the epilepsy eQTL data for the functional interpretation of epilepsy disease-risk variants and, thereby, highlight novel potential causal genes for sporadic epilepsy. In conclusion, an epilepsy-eQTL analysis is superior to normal hippocampal tissue eQTL analyses for identifying the variants and genes underlying epilepsy.

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Section: Resultsmentioning

confidence: 99%

Genetic regulation of gene expression in the epileptic human hippocampus

Mirza

Appleton

Burn

et al. 2017

Human Molecular Genetics

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“…EZO, though the first KCNQ2 channel opener to obtain regulatory approval, has relatively modest potency and selectivity. 34–39 Newer agents, with improved channel subtype-selectivity and greater potency, have been identified, but remain at earlier stages of development. 38,39 Optimal testing of KCNQ2 openers as “precision medicines” for KCNQ2 loss-of-function variants will require early diagnosis, clinical advancement of more potent and selective agents, and prospective trials.…”

Section: Discussionmentioning

confidence: 99%

KCNQ2 encephalopathy

Millichap¹,

Park²,

Tsuchida³

et al. 2016

Neurol Genet

206

112

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Objective:To advance the understanding of KCNQ2 encephalopathy genotype–phenotype relationships and to begin to assess the potential of selective KCNQ channel openers as targeted treatments.Methods:We retrospectively studied 23 patients with KCNQ2 encephalopathy, including 11 treated with ezogabine (EZO). We analyzed the genotype–phenotype relationships in these and 70 previously described patients.Results:The mean seizure onset age was 1.8 ± 1.6 (SD) days. Of the 20 EEGs obtained within a week of birth, 11 showed burst suppression. When new seizure types appeared in infancy (15 patients), the most common were epileptic spasms (n = 8). At last follow-up, seizures persisted in 9 patients. Development was delayed in all, severely in 14. The KCNQ2 variants identified introduced amino acid missense changes or, in one instance, a single residue deletion. They were clustered in 4 protein subdomains predicted to poison tetrameric channel functions. EZO use (assessed by the treating physicians and parents) was associated with improvement in seizures and/or development in 3 of the 4 treated before 6 months of age, and 2 of the 7 treated later; no serious side effects were observed.Conclusions:KCNQ2 variants cause neonatal-onset epileptic encephalopathy of widely varying severity. Pathogenic variants in epileptic encephalopathy are clustered in “hot spots” known to be critical for channel activity. For variants causing KCNQ2 channel loss of function, EZO appeared well tolerated and potentially beneficial against refractory seizures when started early. Larger, prospective studies are needed to enable better definition of prognostic categories and more robust testing of novel interventions.Classification of evidence:This study provides Class IV evidence that EZO is effective for refractory seizures in patients with epilepsy due to KCNQ2 encephalopathy.

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“…Importantly, RTG exhibits little specificity between KCNQ2-5 channel subunits, and the effects arising from KCNQ channels in peripheral tissues, including the bladder, are a recurring problem in patients (Brickel et al 2012;Martyn-St et al 2012). However, RTG has served as an important chemical tool for investigating the therapeutic potential of KCNQ channel modulation, and also as a template for the development of further analogues that may exhibit better subunit selectivity and centrally-restricted actions (Xiong et al 2008;Kalappa et al 2015;Kumar et al 2016).…”

Section: Introductionmentioning

confidence: 99%

Sequence determinants of subtype‐specific actions of KCNQ channel openers

Wang

Yang

Kurata

2016

The Journal of Physiology

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Retigabine (RTG) is the first approved anti-epileptic drug that acts via activation of voltage-gated potassium channels, targeting KCNQ channels that underlie the neuronal M-current. RTG exhibits little specificity between KCNQ2-5 as a result of conservation of a Trp residue in the pore domain that binds to the drug. The RTG analogue ICA-069673 ('ICA73') exhibits much stronger effects on KCNQ2 channels, including a large hyperpolarizing shift of the voltage-dependence of activation, an ∼2-fold enhancement of peak current and pronounced subtype specificity for KCNQ2 over KCNQ3. Based on ICA73 sensitivity of chimeric constructs of the transmembrane segments of KCNQ2 and KCNQ3, this drug appears to interact with the KCNQ2 voltage sensor (S1-S4) rather than the pore region targeted by RTG. KCNQ2 point mutants in the voltage sensor were generated based on KCNQ2/KCNQ3 sequence differences, and screened for ICA73 sensitivity. These experiments reveal that KCNQ2 residues F168 and A181 in the S3 segment are essential determinants of ICA73 subtype specificity. Mutations at either position in KCNQ2 abolish the ICA73-mediated gating shift, but preserve RTG sensitivity. Interestingly, A181P mutant channels show little ICA73-mediated gating shift but retain current potentiation by the drug. Mutations (L198F and P211A), which introduce these critical KCNQ2 residues at corresponding positions in KCNQ3, transplant partial ICA73 sensitivity. These findings demonstrate that RTG and ICA73 act via distinct mechanisms, and also reveal specific residues that underlie subtype specificity of KCNQ channel openers.

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Synthesis and Evaluation of Potent KCNQ2/3-Specific Channel Activators

Cited by 56 publications

References 48 publications

Genetic regulation of gene expression in the epileptic human hippocampus

Genetic regulation of gene expression in the epileptic human hippocampus

KCNQ2 encephalopathy

Sequence determinants of subtype‐specific actions of KCNQ channel openers

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