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Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission.

Authors
Snyder-GL; Vanover-KE; Zhu-H; Miller-DB; O'Callaghan-JP; Tomesch-J; Li-P; Zhang-Q; Krishnan-V; Hendrick-JP; Nestler-EJ; Davis-RE; Wennogle-LP; Mates-S
Source
Psychopharmacol 2015 Feb; 232(3):605-621
NIOSHTIC No.
20045016
Abstract
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 3beta (GSK-3beta) 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.
Keywords
Neuropharmacology; Neurophysiological-effects; Psychopharmacology; Therapeutic-agents; Drug-therapy; Clinical-tests; Chemical-binding; Neurotransmitters; Mental-illness; Cellular-function; Cellular-reactions; Author Keywords: Schizophrenia; DopamineD2 receptor; NMDA receptors; Serotonin 5-HT2A receptor; Social defeat; Nucleus accumbens; Microdialysis; Mesocortical; Nigrostriatal; Serotonin transporter
Contact
G. L. Snyder, Intra-Cellular Therapies, Inc., 3960 Broadway, New York, NY 10032, USA
CODEN
PSCHDL
CAS No.
51-61-6; 50-67-9; 6384-92-5
Publication Date
20150201
Document Type
Journal Article
Email Address
gsnyder@intracellulartherapies.com
Fiscal Year
2015
NTIS Accession No.
NTIS Price
Identifying No.
M092014
Issue of Publication
3
ISSN
0033-3158
NIOSH Division
HELD
Source Name
Psychopharmacology
State
NY; WV; CA
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