title: Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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 (K i  = 0.5 nM) with strong affinity for dopamine (DA) D2 receptors (K i  = 32 nM) and the serotonin transporter (SERT) (K i  = 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Intra-Cellular Therapies, Inc., 3960 Broadway, New York, NY, 10032, USA, gsnyder@intracellulartherapies.com.
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Snyder
authors.forename: Kimberly E
authors.initials: KE
authors.lastname: Vanover
authors.forename: Hongwen
authors.initials: H
authors.lastname: Zhu
authors.forename: Diane B
authors.initials: DB
authors.lastname: Miller
authors.forename: James P
authors.initials: JP
authors.lastname: O'Callaghan
authors.forename: John
authors.initials: J
authors.lastname: Tomesch
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Vaishnav
authors.initials: V
authors.lastname: Krishnan
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Hendrick
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.forename: Robert E
authors.initials: RE
authors.lastname: Davis
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Wennogle
authors.forename: Sharon
authors.initials: S
authors.lastname: Mates
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D055808:Drug Discovery; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology*
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018377:Neurotransmitter Agents; D058830:Serotonin 5-HT2 Receptor Antagonists; D018698:Glutamic Acid