title: Allosteric modulation of sigma-1 receptors elicits anti-seizure activities.
abstract: OBJECTIVE
  Application of orthosteric sigma-1 receptor agonists as anti-seizure drugs has been hindered by questionable efficacy and potential adverse effects. Here, we have investigated the anti-seizure effects of the novel and potent allosteric modulator of sigma-1 receptors, SKF83959 and its derivative SOMCL-668 (3-methyl-phenyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol).
  
  
  METHODS
  The anti-seizure effects of SKF83959 were investigated in three mouse models, maximal electroshock seizures, pentylenetetrazole-induced convulsions and kainic acid-induced 'status epilepticus'. Also, in rats, the cortical epileptiform activity induced by topical application of picrotoxin was recorded in electrocorticograms. In rat hippocampal brain slices, effects of the drugs on the high potassium-evoked epileptiform local field potentials were studied. Anti-seizure activities of SOMCL-668, a newly developed sigma-1 receptor selective allosteric modulator, were also investigated.
  
  
  RESULTS
  SKF83959 (20, 40 mg·kg(-1) ) exhibited anti -seizure actitity in the three mouse models and reduced the cortical epileptiform activity without alteration of spontaneous motor activity and motor coordination. These effects were blocked by the sigma-1 receptor antagonist BD1047, but not the dopamine D1 receptor antagonist SCH23390. SKF83959 alone did not directly inhibit the epileptiform firing of CA3 neurons induced by high potassium in hippocampal slices, but did potentiate inhibition by the orthosteric sigma-1 receptor agonist SKF10047. Lastly, a selective sigma-1 receptor allosteric modulator SOMCL-668, which does not bind to dopamine receptors, exerted similar anti-seizure activities.
  
  
  CONCLUSIONS
  SKF83959 and SOMCL-668 displayed anti-seizure activities, indicating that allosteric modulation of sigma-1 receptors may provide a novel approach for discovering new anti-seizure drugs.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsycho-Disorders and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsycho-Disorders and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Yanke
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsycho-Disorders and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsycho-Disorders and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Neuroscience, School of Medicine at CCNY, City University of New York, New York, NY, USA.
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
authors.affiliation: Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsycho-Disorders and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Xuechu
authors.initials: X
authors.lastname: Zhen
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism; D000097605:Sigma-1 Receptor
chemical_list: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000927:Anticonvulsants; D001552:Benzazepines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C000607367:3-methylphenyl-2,3,4,5-tetrahydro-1H-benzo(d)azepin-7-ol; C080703:SK&F 83959