title: Allosteric Modulation of Sigma-1 Receptors Elicits Rapid Antidepressant Activity.
abstract: OBJECTIVE
  Sigma-1 receptors are involved in the pathophysiological process of several neuropsychiatric diseases such as epilepsy, depression. Allosteric modulation represents an important mechanism for receptor functional regulation. In this study, we examined antidepressant activity of the latest identified novel and selective allosteric modulator of sigma-1 receptor 3-methyl-phenyl-2, 3, 4, 5-tetrahydro-1H-benzo[d]azepin-7-ol (SOMCL-668).
  
  
  RESULTS
  A single administration of SOMCL-668 decreased the immobility time in the forced swimming test (FST) and tailing suspended test in mice, which were abolished by pretreatment of sigma-1 receptor antagonist BD1047. In the chronic unpredicted mild stress (CUMS) model, chronic application of SOMCL-668 rapidly ameliorated anhedonia-like behavior (within a week), accompanying with the enhanced expression of brain-derived neurotrophic factor (BDNF) and phosphorylation of glycogen synthase kinase 3β (GSK3β) (Ser-9) in the hippocampus. SOMCL-668 also rapidly promoted the phosphorylation of GSK3β (Ser-9) in an allosteric manner in vitro. In the cultured primary neurons, SOMCL-668 enhanced the sigma-1 receptor agonist-induced neurite outgrowth and the secretion of BDNF.
  
  
  CONCLUSIONS
  SOMCL-668, a novel allosteric modulator of sigma-1 receptors, elicits a potent and rapid acting antidepressant effect. The present data provide the first evidence that allosteric modulation of sigma-1 receptors may represent a new approach for antidepressant drug discovery.
authors: Jiangsu Key laboratory for Translational Research for Neuropsychiatric Diseases, The Collaborative Innovation Center for Brain Science, College of Pharmaceutical Sciences, Soochow University, Jiangsu, China.|Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Department of Pharmacology, Xuzhou Medical College, Jiangsu, China.
authors: Yun
authors: Y
authors: Wang
authors: Jiangsu Key laboratory for Translational Research for Neuropsychiatric Diseases, The Collaborative Innovation Center for Brain Science, College of Pharmaceutical Sciences, Soochow University, Jiangsu, China.
authors: Lin
authors: L
authors: Guo
authors: Jiangsu Key laboratory for Translational Research for Neuropsychiatric Diseases, The Collaborative Innovation Center for Brain Science, College of Pharmaceutical Sciences, Soochow University, Jiangsu, China.
authors: Hua-Feng
authors: HF
authors: Jiang
authors: Jiangsu Key laboratory for Translational Research for Neuropsychiatric Diseases, The Collaborative Innovation Center for Brain Science, College of Pharmaceutical Sciences, Soochow University, Jiangsu, China.
authors: Long-Tai
authors: LT
authors: Zheng
authors: Department of Medicinal chemistry, Shanghai Institute of Material Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Ao
authors: A
authors: Zhang
authors: Jiangsu Key laboratory for Translational Research for Neuropsychiatric Diseases, The Collaborative Innovation Center for Brain Science, College of Pharmaceutical Sciences, Soochow University, Jiangsu, China.
authors: Xue-Chu
authors: XC
authors: Zhen
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy / Q000209:etiology; D001552:Benzazepines / Q000494:pharmacology / Q000627:therapeutic use*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D046353:Immobility Response, Tonic / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D017480:Receptors, sigma / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological / Q000150:complications / Q000188:drug therapy*; D013550:Swimming / Q000523:psychology; D013997:Time Factors; D000069470:Venlafaxine Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D000097605:Sigma-1 Receptor
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D001552:Benzazepines; D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D010620:Phenazocine; D017480:Receptors, sigma; D000069470:Venlafaxine Hydrochloride; D000097605:Sigma-1 Receptor; C000607367:3-methylphenyl-2,3,4,5-tetrahydro-1H-benzo(d)azepin-7-ol; C012134:SK&F 10047
keywords: Allosteric modulation; Antidepressant; Brain-derived neurotrophic factor; Glycogen synthase kinase 3β; Sigma-1 receptors