GABAkines – Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors

dc.contributor.authorCerne, Rok
dc.contributor.authorLippa, Arnold
dc.contributor.authorPoe, Michael M.
dc.contributor.authorSmith, Jodi L.
dc.contributor.authorJin, Xiaoming
dc.contributor.authorPing, Xingjie
dc.contributor.authorGolani, Lalit K.
dc.contributor.authorCook, James M.
dc.contributor.authorWitkin, Jeffrey M.
dc.contributor.departmentAnatomy and Cell Biology, School of Medicineen_US
dc.date.accessioned2023-02-27T20:42:07Z
dc.date.available2023-02-27T20:42:07Z
dc.date.issued2022-06
dc.description.abstractPositive allosteric modulators of γ-aminobutyric acid-A (GABAA) receptors or GABAkines have been widely used medicines for over 70 years for anxiety, epilepsy, sleep, and other disorders. Traditional GABAkines like diazepam have safety and tolerability concerns that include sedation, motor-impairment, respiratory depression, tolerance and dependence. Multiple GABAkines have entered clinical development but the issue of side-effects has not been fully solved. The compounds that are presently being developed and commercialized include several neuroactive steroids (an allopregnanolone formulation (brexanolone), an allopregnanolone prodrug (LYT-300), Sage-324, zuranolone, and ganaxolone), the α2/3-preferring GABAkine, KRM-II-81, and the α2/3/5-preferring GABAkine PF-06372865 (darigabat). The neuroactive steroids are in clinical development for post-partum depression, intractable epilepsy, tremor, status epilepticus, and genetic epilepsy disorders. Darigabat is in development for epilepsy and anxiety. The imidazodiazepine, KRM-II-81 is efficacious in animal models for the treatment of epilepsy and post-traumatic epilepsy, acute and chronic pain, as well as anxiety and depression. The efficacy of KRM-II-81 in models of pharmacoresistant epilepsy, preventing the development of seizure sensitization, and in brain tissue of intractable epileptic patients bodes well for improved therapeutics. Medicinal chemistry efforts are also ongoing to identify novel and improved GABAkines. The data document gaps in our understanding of the molecular pharmacology of GABAkines that drive differential pharmacological profiles, but emphasize advancements in the ability to successfully utilize GABAA receptor potentiation for therapeutic gain in neurology and psychiatry.en_US
dc.eprint.versionAuthor's manuscripten_US
dc.identifier.citationCerne, R., Lippa, A., Poe, M. M., Smith, J. L., Jin, X., Ping, X., Golani, L. K., Cook, J. M., & Witkin, J. M. (2022). GABAkines – Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors. Pharmacology & Therapeutics, 234, 108035. https://doi.org/10.1016/j.pharmthera.2021.108035en_US
dc.identifier.issn0163-7258en_US
dc.identifier.urihttps://hdl.handle.net/1805/31513
dc.language.isoen_USen_US
dc.publisherElsevieren_US
dc.relation.isversionof10.1016/j.pharmthera.2021.108035en_US
dc.relation.journalPharmacology & Therapeuticsen_US
dc.rightsPublisher Policyen_US
dc.sourceAuthoren_US
dc.subjectAnxietyen_US
dc.subjectEpilepsyen_US
dc.subjectNeuroactive steroidsen_US
dc.subjectDepressionen_US
dc.titleGABAkines – Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptorsen_US
dc.typeArticleen_US
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