{"doi":"10.3389/fcell.2022.912812","title":"Discovery of Small Molecule KCC2 Potentiators Which Attenuate In Vitro Seizure-Like Activity in Cultured Neurons","abstract":"KCC2 is a K + -Cl − cotransporter that is expressed in neurons throughout the central nervous system. Deficits in KCC2 activity have been implicated in a variety of neurological disorders, including epilepsy, chronic pain, autism spectrum disorders, and Rett syndrome. Therefore, it has been hypothesized that pharmacological potentiation of KCC2 activity could provide a treatment for these disorders. To evaluate the therapeutic potential of pharmacological KCC2 potentiation, drug-like, selective KCC2 potentiators are required. Unfortunately, the lack of such tools has greatly hampered the investigation of the KCC2 potentiation hypothesis. Herein, we describe the discovery and characterization of a new class of small-molecule KCC2 potentiator. This newly discovered class exhibits KCC2-dependent activity and a unique mechanistic profile relative to previously reported small molecules. Furthermore, we demonstrate that KCC2 potentiation by this new class of KCC2 potentiator attenuates seizure-like activity in neuronal-glial co-cultures. Together, our results provide evidence that pharmacological KCC2 potentiation, by itself, is sufficient to attenuate neuronal excitability in an in vitro model that is sensitive to anti-epileptic drugs. Our findings and chemical tools are important for evaluating the promise of KCC2 as a therapeutic target and could lay a foundation for the development of KCC2-directed therapeutics for multiple neurological disorders.","journal":"Frontiers in Cell and Developmental Biology","year":2022,"id":255464,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9519,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":317768,"name":"Kwangho Kim","orcid":"0000-0001-9387-7642","position":1,"is_corresponding":false},{"id":327998,"name":"Yu Du","orcid":"0000-0002-4114-396X","position":2,"is_corresponding":false},{"id":327995,"name":"Brittany D. Spitznagel","orcid":"0000-0003-4172-4147","position":3,"is_corresponding":false},{"id":317764,"name":"Gary A. Sulikowski","orcid":"0000-0002-1067-0767","position":4,"is_corresponding":false},{"id":275675,"name":"Eric Delpire","orcid":"0000-0002-3702-1599","position":5,"is_corresponding":false},{"id":328002,"name":"C. David Weaver","orcid":"0000-0002-6886-1195","position":6,"is_corresponding":false},{"id":330022,"name":"Francis J. Prael","orcid":null,"position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T00:25:17.224217Z","pmid":"35813195","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":[]}