Experimental GABA A Receptor Agonists and Allosteric Modulators for the Treatment of Focal Epilepsy

References

• Chuang S-H, Reddy DS. Genetic and molecular regulation of extrasynaptic GABA-A receptors in the brain: therapeutic insights for epilepsy. J Pharmacol Exp Ther. 2018;364(2):180–197. doi:10.1124/jpet.117.244673
   Web of Science ®Google Scholar
• Vargas RA. The GABAergic system: an overview of physiology, physiopathology and therapeutics. Int J Clin Pharmacol Pharmacother. 2018;4:143.
   Google Scholar
• Hernandez CC, Macdonald RL. A structural look at GABAA receptor mutations linked to epilepsy syndromes. Brain Res. 2019;1714:234–247. doi:10.1016/j.brainres.2019.03.004
   Web of Science ®Google Scholar
• Abou-Khalil BW. Update on antiepileptic drugs 2019. Continuum. 2019;25(2):508–536. doi:10.1212/CON.0000000000000715
   Google Scholar
• Laxer KD, Trinka E, Hirsch LJ, et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav. 2014;37:59–70. doi:10.1016/j.yebeh.2014.05.031
   PubMed Web of Science ®Google Scholar
• Oller LFV. The prevalence of different types of epilepsy in clinical practice. Rev Neurol. 2002;34(6):526–531.
   Web of Science ®Google Scholar
• Sigel E, Steinmann ME. Structure, function, and modulation of GABA(A) receptors. J Biol Chem. 2012;287(48):40224–40231. doi:10.1074/jbc.R112.386664
   PubMed Web of Science ®Google Scholar
• Olsen RW, Sieghart W. International union of pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Pharmacol Rev. 2008;60(3):243–260. doi:10.1124/pr.108.00505
   PubMed Web of Science ®Google Scholar
• Sieghart W. Structure, pharmacology, and function of GABAA receptor subtypes. Adv Pharmacol. 2006;54:231–263.
   PubMedGoogle Scholar
• Zhu S, Noviello CM, Teng J, et al. Structure of a human synaptic GABAA receptor. Nature. 2018;559(7712):67–72. doi:10.1038/s41586-018-0255-3
   PubMed Web of Science ®Google Scholar
• Chua HC, Chebib M. GABAA receptors and the diversity in their structure and pharmacology. Adv Pharmacol. 2017;79:1–34.
   PubMedGoogle Scholar
• Olsen RW. GABAA receptor: positive and negative allosteric modulators. Neuropharmacology. 2018;136(Pt A):10–22.
   Web of Science ®Google Scholar
• Sieghart W. Chapter three - allosteric modulation of GABAA receptors via multiple drug-binding sites. In: Rudolph U, editor. Advances in Pharmacology [Internet]. Academic Press; 2015: 53–96. (Diversity and functions of GABA receptors: a tribute to Hanns Möhler, part A; vol. 72). Available from: http://www.sciencedirect.com/science/article/pii/S1054358914000374. Accessed February 24, 2021.
   Google Scholar
• Lorenz-Guertin JM, Jacob TC. GABA type a receptor trafficking and the architecture of synaptic inhibition. Dev Neurobiol. 2018;78(3):238–270.
   Web of Science ®Google Scholar
• Olsen RW. Allosteric ligands and their binding sites define γ-aminobutyric acid (GABA) type A receptor subtypes. Adv Pharmacol. 2015;73:167–202.
   Google Scholar
• Changeux J-P, Christopoulos A. Allosteric modulation as a unifying mechanism for receptor function and regulation. Diabetes Obes Metab. 2017;19(Suppl 1):4–21. doi:10.1111/dom.12959
   Web of Science ®Google Scholar
• Krogsgaard-Larsen P, Frølund B, Liljefors T. Specific GABA(A) agonists and partial agonists. Chem Rec. 2002;2(6):419–430. doi:10.1002/tcr.10040
   Web of Science ®Google Scholar
• Falch E, Jacobsen P, Krogsgaard-Larsen P, Curtis DR. GABA-mimetic activity and effects on diazepam binding of aminosulphonic acids structurally related to piperidine-4-sulphonic acid. J Neurochem. 1985;44(1):68–75. doi:10.1111/j.1471-4159.1985.tb07114.x
   Web of Science ®Google Scholar
• Hansen SL, Ebert B, Fjalland B, Kristiansen U. Effects of GABA(A) receptor partial agonists in primary cultures of cerebellar granule neurons and cerebral cortical neurons reflect different receptor subunit compositions. Br J Pharmacol. 2001;133(4):539–549. doi:10.1038/sj.bjp.0704121
   Web of Science ®Google Scholar
• Johnston GAR. Advantages of an antagonist: bicuculline and other GABA antagonists. Br J Pharmacol. 2013;169(2):328–336. doi:10.1111/bph.12127
   PubMed Web of Science ®Google Scholar
• Masiulis S, Desai R, Uchański T, et al. GABAA receptor signalling mechanisms revealed by structural pharmacology. Nature. 2019;565(7740):454–459. doi:10.1038/s41586-018-0832-5
   PubMed Web of Science ®Google Scholar
• Kirkness EF, Turner AJ. The gamma-aminobutyrate/benzodiazepine receptor from pig brain. Enhancement of gamma-aminobutyrate-receptor binding by the anaesthetic propanidid. Biochem J. 1986;233(1):259–264. doi:10.1042/bj2330259
   Web of Science ®Google Scholar
• Dawson GR, Wafford KA, Smith A, et al. Anticonvulsant and adverse effects of avermectin analogs in mice are mediated through the gamma-aminobutyric acid(A) receptor. J Pharmacol Exp Ther. 2000;295(3):1051–1060.
   PubMed Web of Science ®Google Scholar
• Kent DE, Savechenkov PY, Bruzik KS, Miller KW. Binding site location on GABAA receptors determines whether mixtures of intravenous general anaesthetics interact synergistically or additively in vivo. Br J Pharmacol. 2019;176(24):4760–4772. doi:10.1111/bph.14843
   Web of Science ®Google Scholar
• Baur R, Gertsch J, Sigel E. The cannabinoid CB1 receptor antagonists rimonabant (SR141716) and AM251 directly potentiate GABA(A) receptors. Br J Pharmacol. 2012;165(8):2479–2484. doi:10.1111/j.1476-5381.2011.01405.x
   Web of Science ®Google Scholar
• Sigel E, Baur R, Rácz I, et al. The major central endocannabinoid directly acts at GABA(A) receptors. Proc Natl Acad Sci U S A. 2011;108(44):18150–18155. doi:10.1073/pnas.1113444108
   PubMed Web of Science ®Google Scholar
• Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia. 2017;58(4):512–521. doi:10.1111/epi.13709
   PubMed Web of Science ®Google Scholar
• Avoli M, D’Antuono M, Louvel J, et al. Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro. Prog Neurobiol. 2002;68(3):167–207. doi:10.1016/S0301-0082(02)00077-1
   PubMed Web of Science ®Google Scholar
• Curia G, Lucchi C, Vinet J, et al. Pathophysiogenesis of mesial temporal lobe epilepsy: is prevention of damage antiepileptogenic? Curr Med Chem. 2014;21(6):663–688. doi:10.2174/0929867320666131119152201
   PubMed Web of Science ®Google Scholar
• Treiman DM. GABAergic mechanisms in epilepsy. Epilepsia. 2001;42(Suppl 3):8–12. doi:10.1046/j.1528-1157.2001.042suppl.3008.x
   PubMed Web of Science ®Google Scholar
• Fritschy JM, Kiener T, Bouilleret V, Loup F. GABAergic neurons and GABA(A)-receptors in temporal lobe epilepsy. Neurochem Int. 1999;34(5):435–445. doi:10.1016/S0197-0186(99)00040-6
   Web of Science ®Google Scholar
• Stamboulian-Platel S, Legendre A, Chabrol T, et al. Activation of GABAA receptors controls mesiotemporal lobe epilepsy despite changes in chloride transporters expression: in vivo and in silico approach. Exp Neurol. 2016;284(Pt A):11–28. doi:10.1016/j.expneurol.2016.07.009
   Web of Science ®Google Scholar
• Mehta P, Srivastava S, Sharma M, et al. Identification of chemically diverse GABAA agonists as potential anti-epileptic agents using structure-guided virtual screening, ADMET, quantum mechanics and clinical validation through off-target analysis. Int J Biol Macromol. 2018;119:1113–1128. doi:10.1016/j.ijbiomac.2018.08.032
   PubMed Web of Science ®Google Scholar
• Ochoa-de la Paz L, Zenteno E, Gulias-Cañizo R, Quiroz-Mercado H. Taurine and GABA neurotransmitter receptors, a relationship with therapeutic potential? Expert Rev Neurother. 2019;19(4):289–291. doi:10.1080/14737175.2019.1593827
   PubMed Web of Science ®Google Scholar
• Li Q, Guo J-C, Jin H-B, et al. Involvement of taurine in penicillin-induced epilepsy and anti-convulsion of acupuncture: a preliminary report. Acupunct Electrother Res. 2005;30(1–2):1–14. doi:10.3727/036012905815901325
   Web of Science ®Google Scholar
• Taranukhin AG, Saransaari P, Kiianmaa K, et al. Comparison of toxicity of taurine and GABA in combination with alcohol in 7-day-old mice. Adv Exp Med Biol. 2017;975(Pt 2):1021–1033.
   Web of Science ®Google Scholar
• Curran CP, Marczinski CA. Taurine, caffeine, and energy drinks: reviewing the risks to the adolescent brain. Birth Defects Res. 2017;109(20):1640–1648. doi:10.1002/bdr2.1177
   Web of Science ®Google Scholar
• Witkin JM, Smith JL, Ping X, et al. Bioisosteres of ethyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo [1,5-a][1,4]diazepine-3-carboxylate (HZ-166) as novel alpha 2,3 selective potentiators of GABAA receptors: improved bioavailability enhances anticonvulsant efficacy. Neuropharmacology. 2018;137:332–343. doi:10.1016/j.neuropharm.2018.05.006
   Web of Science ®Google Scholar
• Nomura T, Hawkins NA, Kearney JA, et al. Potentiating α2 subunit containing perisomatic GABAA receptors protects against seizures in a mouse model of Dravet syndrome. J Physiol. 2019;597(16):4293–4307. doi:10.1113/JP277651
   PubMed Web of Science ®Google Scholar
• Duveau V, Buhl DL, Evrard A, et al. Pronounced antiepileptic activity of the subtype-selective GABAA -positive allosteric modulator PF-06372865 in the GAERS absence epilepsy model. CNS Neurosci Ther. 2019;25(2):255–260. doi:10.1111/cns.13046
   PubMed Web of Science ®Google Scholar
• Rundfeldt C, Löscher W. The pharmacology of imepitoin: the first partial benzodiazepine receptor agonist developed for the treatment of epilepsy. CNS Drugs. 2014;28(1):29–43. doi:10.1007/s40263-013-0129-z
   PubMed Web of Science ®Google Scholar
• Löscher W, Potschka H, Rieck S, et al. Anticonvulsant efficacy of the low-affinity partial benzodiazepine receptor agonist ELB 138 in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures. Epilepsia. 2004;45(10):1228–1239. doi:10.1111/j.0013-9580.2004.21204.x
   Web of Science ®Google Scholar
• Reddy DS, Jian K. The testosterone-derived neurosteroid androstanediol is a positive allosteric modulator of GABAA receptors. J Pharmacol Exp Ther. 2010;334(3):1031–1041. doi:10.1124/jpet.110.169854
   Web of Science ®Google Scholar
• Miziak B, Chrościńska-Krawczyk M, Czuczwar SJ. Neurosteroids and seizure activity. Front Endocrinol. 2020;11:541802. doi:10.3389/fendo.2020.541802
   PubMed Web of Science ®Google Scholar
• Lucchi C, Costa AM, Rustichelli C, Biagini G. Allopregnanolone and pregnanolone are reduced in the hippocampus of epileptic rats, but only allopregnanolone correlates with the seizure frequency. Neuroendocrinology. 2020. doi:10.1159/000509093
   Web of Science ®Google Scholar
• Lévesque M, Biagini G, Avoli M. Neurosteroids and focal epileptic disorders. Int J Mol Sci. 2020;21(24):9391. doi:10.3390/ijms21249391
   Web of Science ®Google Scholar
• Pugnaghi M, Monti G, Biagini G, Meletti S. Temporal lobe epilepsy exacerbation during pharmacological inhibition of endogenous neurosteroid synthesis. BMJ Case Rep. 2013;2013(feb19 1):bcr2012008204. doi:10.1136/bcr-2012-008204
   Google Scholar
• Trivisano M, Lucchi C, Rustichelli C, et al. Reduced steroidogenesis in patients with PCDH19-female limited epilepsy. Epilepsia. 2017;58(6):e91–5. doi:10.1111/epi.13772
   PubMed Web of Science ®Google Scholar
• Meletti S, Lucchi C, Monti G, et al. Decreased allopregnanolone levels in cerebrospinal fluid obtained during status epilepticus. Epilepsia. 2017;58(2):e16–20. doi:10.1111/epi.13625
   PubMed Web of Science ®Google Scholar
• Pernea M, Sutcliffe AG. Clobazam and its use in epilepsy. Pediatr Rep. 2016;8(2):6516. doi:10.4081/pr.2016.6516
   PubMedGoogle Scholar
• Arya R, Giridharan N, Anand V, Garg SK. Clobazam monotherapy for focal or generalized seizures. Cochrane Database Syst Rev. 2018;11(7):CD009258.
   Google Scholar
• Gimigliano F. Is clobazam monotherapy effective and safe in people with focal or generalized seizures? A cochrane review summary with commentary. Dev Med Child Neurol. 2020;62(6):670–672. doi:10.1111/dmcn.14539
   Web of Science ®Google Scholar
• Gauthier AC, Mattson RH. Clobazam: a safe, efficacious, and newly rediscovered therapeutic for epilepsy. CNS Neurosci Ther. 2015;21(7):543–548. doi:10.1111/cns.12399
   PubMed Web of Science ®Google Scholar
• Andrade R, García-Espinosa A, Machado-Rojas A, et al. A prospective, open, controlled and randomised study of clobazam versus carbamazepine in patients with frequent episodes of rolandic epilepsy. Rev Neurol. 2009;49(11):581–586.
   Web of Science ®Google Scholar
• Vidaurre J, Herbst J. New antiepileptic drugs. Medicina (Mex). 2019;79(Suppl 3):48–53.
   Google Scholar
• Jankovic S, Lukic S. Antiepileptic potential of ganaxolone. Vojnosanit Pregl. 2016;74:157.
   Web of Science ®Google Scholar
• Bialer M, Johannessen SI, Koepp MJ, et al. Progress report on new antiepileptic drugs: a summary of the fifteenth eilat conference on new antiepileptic drugs and devices (EILAT XV). II. Drugs in more advanced clinical development. Epilepsia. 2020;61(11):2365–2385. doi:10.1111/epi.16726
   PubMed Web of Science ®Google Scholar
• Ligsay A, Van Dijck A, Nguyen DV, et al. A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome. J Neurodev Disord. 2017;9(1):26. doi:10.1186/s11689-017-9207-8
   PubMed Web of Science ®Google Scholar
• Sperling MR, Klein P, Tsai J. Randomized, double-blind, placebo-controlled Phase 2 study of ganaxolone as add-on therapy in adults with uncontrolled partial-onset seizures. Epilepsia. 2017;58(4):558–564. doi:10.1111/epi.13705
   PubMed Web of Science ®Google Scholar
• Boada CM, French JA, Dumanis SB. Proceedings of the 15th antiepileptic drug and device trials meeting: state of the science. Epilepsy Behav. 2020;111:107189. doi:10.1016/j.yebeh.2020.107189
   Web of Science ®Google Scholar
• Simen A, Whitlock M, Qiu R, et al. An 8-week, randomized, phase 2, double-blind, sequential parallel-group comparison study of two dose levels of the GABAA positive allosteric modulator PF-06372865 compared with placebo as an adjunctive treatment in outpatients with inadequate response to standard of care for generalized anxiety disorder. J Clin Psychopharmacol. 2019;39(1):20–27. doi:10.1097/JCP.0000000000000997
   PubMed Web of Science ®Google Scholar
• Gurrell R, Gorman D, Whitlock M, et al. Photosensitive epilepsy: robust clinical efficacy of a selective GABA potentiator. Neurology. 2019;92(15):e1786–95. doi:10.1212/WNL.0000000000007271
   PubMed Web of Science ®Google Scholar
• van Amerongen G, Siebenga PS, Gurrell R, et al. Analgesic potential of PF-06372865, an α2/α3/α5 subtype-selective GABAA partial agonist, in humans. Br J Anaesth. 2019;123(2):e194–203. doi:10.1016/j.bja.2018.12.006
   PubMed Web of Science ®Google Scholar
• Wood M, Daniels V, Provins L, et al. Pharmacological profile of the novel antiepileptic drug candidate padsevonil: interactions with synaptic vesicle 2 proteins and the GABAA receptor. J Pharmacol Exp Ther. 2020;372(1):1–10. doi:10.1124/jpet.119.261149
   PubMed Web of Science ®Google Scholar
• Muglia P, Hannestad J, Brandt C, et al. Padsevonil randomized phase IIa trial in treatment-resistant focal epilepsy: a translational approach. Brain Commun. 2020;2(2):fcaa183. doi:10.1093/braincomms/fcaa183
   PubMedGoogle Scholar
• Mula M. Emerging drugs for focal epilepsy. Expert Opin Emerg Drugs. 2018;23(3):243–249. doi:10.1080/14728214.2018.1527903
   PubMed Web of Science ®Google Scholar
• Clobazam wockhardt 1mg/ml oral suspension - summary of product characteristics (SmPC) - (emc) [Internet]. [cited December 9, 2020]. Available from: https://www.medicines.org.uk/emc/product/11632/smpc. Accessed February 24, 2021.
   Google Scholar
• Clobazam oral suspension - FDA prescribing information, side effects and uses [Internet]. Drugs.com. [cited December 9, 2020]. Available from: https://www.drugs.com/pro/clobazam-oral-suspension.html. Accessed February 24, 2021.
   Google Scholar
• Marinus launches expanded access program for ganaxolone treatment in CDKL5 deficiency disorder [Internet]. [cited December 9, 2020]. Available from: https://ir.marinuspharma.com/news/news-details/2020/Marinus-Launches-Expanded-Access-Program-for-Ganaxolone-Treatment-in-CDKL5-Deficiency-Disorder/default.aspx. Accessed February 24, 2021.
   Google Scholar
• Sullivan J, Specchio N, Chez MG, et al. Preliminary evidence of a predictive clinical biomarker in pcdh19-related epilepsy: significant treatment effect of ganaxolone in biomarker-positive patients. Annual meeting abstracts [Internet]. American Epilepsy Society; 2018 [cited February 11, 2021]. Available from: https://www.aesnet.org/meetings_events/annual_meeting_abstracts/view/502507. Accessed February 24, 2021.
   Google Scholar
• Cerevel Therapeutics, LLC. A randomized, double-blind, placebo-controlled, parallel group, multicenter trial of CVL-865 as adjunctive therapy in adults with drug-resistant focal onset seizures (REALIZE trial) [Internet]. clinicaltrials.gov; 2020 [cited December 8, 2020]. Report No.: NCT04244175. Available from: https://clinicaltrials.gov/ct2/show/NCT04244175. Accessed February 24, 2021.
   Google Scholar
• UCB Biopharma SRL. A multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of padsevonil as adjunctive treatment of focal-onset seizures in adult subjects with drug-resistant epilepsy [Internet]. clinicaltrials.gov; 2020 [cited December 8, 2020]. Report No.: record/NCT03739840. Available from: https://clinicaltrials.gov/ct2/show/record/NCT03739840. Accessed February 24, 2021.
   Google Scholar
• Key events – UCB integrated annual report 2019 [Internet]. Integrated annual report; 2019 [cited December 9, 2020]. Available from: https://reports.ucb.com/2019/integrated-annual-report/financials/business-performance-review/key-events.html. Accessed February 24, 2021.
   Google Scholar