{"doi":"10.1111/epi.18092","title":"Identification of a new retigabine derivative with improved photostability for selective activation of neuronal Kv7 channels and antiseizure activity","abstract":"<jats:title>Abstract</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>Pharmacological activation of neuronal Kv7 channels by the antiepileptic drug retigabine (RTG; ezogabine) has been proven effective in treating partial epilepsy. However, RTG was withdrawn from the market due to the toxicity caused by its phenazinium dimer metabolites, leading to peripheral skin discoloration and retinal abnormalities. To address the undesirable metabolic properties of RTG and prevent the formation of phenazinium dimers, we made chemical modifications to RTG, resulting in a new RTG derivative, 1025c, <jats:italic>N,N′</jats:italic>‐{4‐[(4‐fluorobenzyl) (prop‐2‐yn‐1‐yl)amino]‐1,2‐phenylene}bis(3,3‐dimethylbutanamide).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Whole‐cell recordings were used to evaluate Kv7 channel openers. Site‐directed mutagenesis and molecular docking were adopted to investigate the molecular mechanism underlying 1025c and Kv7.2 interactions. Mouse seizure models of maximal electroshock (MES), subcutaneous pentylenetetrazol (scPTZ), and PTZ‐induced kindling were utilized to test compound antiepileptic activity.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The novel compound 1025c selectively activates whole‐cell Kv7.2/7.3 currents in a concentration‐dependent manner, with half‐maximal effective concentration of .91 ± .17 μmol·L<jats:sup>−1</jats:sup>. The 1025c compound also causes a leftward shift in Kv7.2/7.3 current activation toward a more hyperpolarized membrane potential, with a shift of the half voltage of maximal activation (ΔV<jats:sub>1/2</jats:sub>) of −18.6 ± 3.0 mV. Intraperitoneal administration of 1025c demonstrates dose‐dependent antiseizure activities in assays of MES, scPTZ, and PTZ‐induced kindling models. Moreover, through site‐directed mutagenesis combined with molecular docking, a key residue Trp236 has been identified as critical for 1025c‐mediated activation of Kv7.2 channels. Photostability experiments further reveal that 1025c is more photostable than RTG and is unable to dimerize.</jats:p></jats:sec><jats:sec><jats:title>Significance</jats:title><jats:p>Our findings demonstrate that 1025c exhibits potent and selective activation of neuronal Kv7 channels without being metabolized to phenazinium dimers, suggesting its developmental potential as an antiseizure agent for therapy.</jats:p></jats:sec>","journal":"Epilepsia","year":2024,"id":640612,"datarank":0.42498200160843247,"base_score":2.833213344056216,"endowment":2.833213344056216,"self_citation_contribution":0.42498200160843247,"citation_network_contribution":0.0,"self_endowment_contribution":0.42498200160843247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1118319,"name":"Zhen Qiao","orcid":"0000-0002-7716-915X","position":1,"is_corresponding":false},{"id":1664983,"name":"Kun Luan","orcid":null,"position":2,"is_corresponding":false},{"id":712059,"name":"Wei Xiang","orcid":"0000-0002-4443-3620","position":3,"is_corresponding":false},{"id":1664984,"name":"Xiuying Chang","orcid":null,"position":4,"is_corresponding":false},{"id":1655212,"name":"Yanru Zhang","orcid":"0000-0001-6266-8020","position":5,"is_corresponding":false},{"id":1664985,"name":"Ningning Wei","orcid":"0000-0002-6983-8982","position":6,"is_corresponding":false},{"id":163006,"name":"KeWei Wang","orcid":"0000-0001-7023-9998","position":7,"is_corresponding":false},{"id":722830,"name":"Hongbin Wang","orcid":"0009-0008-2807-1181","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Identification of a new retigabine derivative with improved photostability for selective activation of neuronal Kv7 channels and antiseizure activity","abstract":"Abstract Objective Pharmacological activation of neuronal Kv7 channels by the antiepileptic drug retigabine (RTG; ezogabine) has been proven effective in treating partial epilepsy. However, RTG was withdrawn from the market due to the toxicity caused by its phenazinium dimer metabolites, leading to peripheral skin discoloration and retinal abnormalities. To address the undesirable metabolic properties of RTG and prevent the formation of phenazinium dimers, we made chemical modifications to RTG, resulting in a new RTG derivative, 1025c, N,N′ ‐{4‐[(4‐fluorobenzyl) (prop‐2‐yn‐1‐yl)amino]‐1,2‐phenylene}bis(3,3‐dimethylbutanamide). Methods Whole‐cell recordings were used to evaluate Kv7 channel openers. Site‐directed mutagenesis and molecular docking were adopted to investigate the molecular mechanism underlying 1025c and Kv7.2 interactions. Mouse seizure models of maximal electroshock (MES), subcutaneous pentylenetetrazol (scPTZ), and PTZ‐induced kindling were utilized to test compound antiepileptic activity. Results The novel compound 1025c selectively activates whole‐cell Kv7.2/7.3 currents in a concentration‐dependent manner, with half‐maximal effective concentration of .91 ± .17 μmol·L −1 . The 1025c compound also causes a leftward shift in Kv7.2/7.3 current activation toward a more hyperpolarized membrane potential, with a shift of the half voltage of maximal activation (ΔV 1/2 ) of −18.6 ± 3.0 mV. Intraperitoneal administration of 1025c demonstrates dose‐dependent antiseizure activities in assays of MES, scPTZ, and PTZ‐induced kindling models. Moreover, through site‐directed mutagenesis combined with molecular docking, a key residue Trp236 has been identified as critical for 1025c‐mediated activation of Kv7.2 channels. Photostability experiments further reveal that 1025c is more photostable than RTG and is unable to dimerize. Significance Our findings demonstrate that 1025c exhibits potent and selective activation of neuronal Kv7 channels without being metabolized to phenazinium dimers, suggesting its developmental potential as an antiseizure agent for therapy.","is_dataset_classified":null,"base_score":2.833213344056216,"endowment":2.833213344056216,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39140981","pmcid":null,"openalex_id":"https://openalex.org/W4401577374","authors":[],"funders":[{"funder_name":"National Natural Science Foundation of China","grant_id":"81973299","title":null},{"funder_name":"China Postdoctoral Science Foundation","grant_id":"2021M691698","title":null},{"funder_name":"Natural Science Foundation of Shandong Province","grant_id":"ZR202111150135","title":null}],"total_grants":3,"fwci":2.585,"citation_percentile":0.90529041,"influential_citations":0,"citation_trend":[{"year":2025,"count":8},{"year":2026,"count":8}],"oa_status":"bronze","license":null,"oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/epi.18092","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/epi.18092","host_type":"publisher"},{"url":"https://doi.org/10.1111/epi.18092","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39140981","host_type":"repository"}],"fields_of_study":["Ion channel regulation and function","Neuroscience and Neuropharmacology Research","Cardiac electrophysiology and arrhythmias"],"mesh_terms":["Animals","Anticonvulsants","Carbamates","Disease Models, Animal","Dose-Response Relationship, Drug","Electroshock","Humans","Male","Mice, Inbred C57BL","Neurons","Pentylenetetrazole","Phenylenediamines","Seizures","Mutagenesis, Site-Directed","Patch-Clamp Techniques","Mice","KCNQ2 Potassium Channel","KCNQ3 Potassium Channel","HEK293 Cells","Molecular Docking Simulation"],"keywords":["Chemistry","Pentylenetetrazol","Pharmacology","Anticonvulsant","Kindling model","Stereochemistry","Biophysics","Epilepsy","Neuroscience","Medicine","Biology","Molecular docking","Kv7 Channels","Mouse Seizure Models","Whole‐cell Patch Clamp Recordings"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-07T13:03:00.098006Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}