Functional Profile of a Novel Modulator of Serotonin, Dopamine, and Glutamate Neurotransmission

Details

• Journal Article:
  Psychopharmacology (Berl)
• Personal Author:
  Snyder, Gretchen L. ; Vanover, Kimberly E. ; Zhu, Hongwen ; Miller, Diane B. ; O’Callaghan, James P. ; Tomesch, John ; Li, Peng ; Zhang, Qiang ; Krishnan, Vaishnav ; Hendrick, Joseph P. ; Nestler, Eric J. ; Davis, Robert E. ; Wennogle, Lawrence P. ; Mates, Sharon
• Description:
  Rationale
  
  Schizophrenia remains among the most prevalent neuropsychiatric disorders, and current treatment options are accompanied by unwanted side effects. New treatments that better address core features of the disease with minimal side effects are needed.
  
  Objectives
  
  As a new therapeutic approach, 1-(4-fluoro-phenyl)-4-((6bR, 10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one (ITI-007) is currently in human clinical trials for the treatment of schizophrenia. Here, we characterize the preclinical functional activity of ITI-007.
  
  Results
  
  ITI-007 is a potent 5-HT2A receptor ligand (Ki = 0.5 nM) with strong affinity for dopamine (DA) D2 receptors (Ki = 32 nM) and the serotonin transporter (SERT) (Ki = 62 nM) but negligible binding to receptors (e.g., H1 histaminergic, 5-HT2C, and muscarinic) associated with cognitive and metabolic side effects of antipsychotic drugs. In vivo it is a 5-HT2A antagonist, blocking (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced headtwitch in mice with an inhibitory dose 50 (ID50) = 0.09 mg/kg, per oral (p.o.), and has dual properties at D2 receptors, acting as a postsynaptic D2 receptor antagonist to block D-amphetamine hydrochloride (D-AMPH) hyperlocomotion (ID50 = 0.95 mg/kg, p.o.), yet acting as a partial agonist at presynaptic striatal D2 receptors in assays measuring striatal DA neurotransmission. Further, in microdialysis studies, this compound significantly and preferentially enhances mesocortical DA release. At doses relevant for antipsychotic activity in rodents, ITI-007 has no demonstrable cataleptogenic activity. ITI-007 indirectly modulates glutamatergic neurotransmission by increasing phosphorylation of GluN2B-type N-methyl-d-aspartate (NMDA) receptors and preferentially increases phosphorylation of glycogen synthase kinase 3β (GSK-3β) in mesolimbic/mesocortical dopamine systems.
  
  Conclusion
  
  The combination of in vitro and in vivo activities of this compound support its development for the treatment of schizophrenia and other psychiatric and neurologic disorders.
  
  
• Subjects:
  Dopamine Glutamate Nervous System Serotonin
• Keywords:
  Author Keywords: Schizophrenia; DopamineD2 Receptor; NMDA Receptors; Serotonin 5-HT2A Receptor; Social Defeat; Nucleus Accumbens; Microdialysis; Mesocortical; Nigrostriatal; Serotonin Transporter Neuropharmacology; Neurophysiological-effects; Psychopharmacology; Therapeutic-agents; Drug-therapy; Clinical-tests; Chemical-binding; Neurotransmitters; Mental-illness; Cellular-function; Cellular-reactions;
• Source:
  Psychopharmacology (Berl). 232:605-621.
• Document Type:
  Text
• Funding:
  P50 MH090963/MH/NIMH NIH HHS/United States ; P50 MH096890/MH/NIMH NIH HHS/United States ; R01 MH051399/MH/NIMH NIH HHS/United States
• Genre:
  Journal Article
• Place as Subject:
  California ; New York ; OSHA Region 2 ; OSHA Region 3 ; OSHA Region 9 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  17 pdf pages
• Volume:
  232
• Issue:
  3
• NIOSHTIC Number:
  nn:20045016
• CAS Registry Number:
  Dopamine (CAS RN 51-61-6) ; NMDA (CAS RN 6384-92-5) ; Serotonin (CAS RN 50-67-9)
• Federal Fiscal Year:
  2015
• Peer Reviewed:
  True
• Collection(s):
  CDC Public Access National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:886a87a24b9ad5bd377eb549f71c58b2aecb45676b6adc0b2e54d55afa3c1fa93441af73fd2422025af3c4af3c08d983269d3d3c2c4aeb6836df72071f204979
• Download URL:
  https://stacks.cdc.gov/view/cdc/27940/cdc_27940_DS1.pdf
• File Type:
  [PDF - 939.83 KB ]