Antipsychotic Agents

Brown, Jeffrey M.; Li, Jie Jack; Sinz, Michael

doi:10.1002/0471266949.bmc103.pub2

Burger's Medicinal Chemistry and Drug Discovery 2010

DOI: 10.1002/0471266949.bmc103.pub2

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Antipsychotic Agents

Jeffrey M. Brown¹,

Jie Jack Li²,

Michael Sinz³

Abstract: The medicinal chemistry of antipsychotic agents is reviewed in this chapter. The definition of schizophrenia is summarized in two categories, namely, symptom domains and pathology. An overview is given for antipsychotic medications including their clinical applications and side effects. This chapter also describes many animal models for schizophrenia. After an introduction of the FDA approved antipsychotic drugs, the structure–activity relationship, pharmacokinetics, biotransformation, and drug–drug interactio… Show more

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2013

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“…Schizophrenia is a complex neuropsychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive deficits (Brown et al . ). While current antipsychotic medications are effective at alleviating positive symptoms, treatment of negative symptoms and cognitive deficits remain an unmet medical need.…”

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confidence: 97%

In vitro Characterization of a small molecule inhibitor of the alanine serine cysteine transporter ‐1 (SLC7A10)

Brown

Hunihan

Prack

et al. 2013

Journal of Neurochemistry

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NMDA receptor hypofunction is hypothesized to contribute to cognitive deficits associated with schizophrenia. Since direct activation of NMDA receptors is associated with serious adverse effects, modulation of the NMDA co-agonists, glycine or D-serine, represents a viable alternative therapeutic approach. Indeed, clinical trials with glycine and D-serine have shown positive results, although concerns over toxicity related to the high-doses required for efficacy remain. Synaptic concentrations of D-serine and glycine are regulated by the amino acid transporter alanine serine cysteine transporter-1 (asc-1). Inhibition of asc-1 would increase synaptic D-serine and possibly glycine, eliminating the need for high-dose Schizophrenia is a complex neuropsychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive deficits (Brown et al. 2010). While current antipsychotic medications are effective at alleviating positive symptoms, treatment of negative symptoms and cognitive deficits remain an unmet medical need. Cognitive deficits are hypothesized to results from an under-activation or hypofunction of NMDA receptors. This hypothesis is based on data in human subjects, demonstrating that the pharmacological blockade of NMDA receptors produces cognitive deficits that parallel those seen in schizophrenia patients (Malhotra et al. 1996;Adler et al. 1999). These findings are supported by pre-clinical data demonstrating that inhibition of NMDA receptor function disrupts measures of cognition (Jentsch et al. 1997a,b;Stefani and Moghaddam 2005). Based on these data, development of newer medications has largely focused on improving NMDA receptor function. However, since direct pharmacological activation of NMDA receptors leads to over-excitation and seizures, indirect modulation of NMDA receptors at one of the many regulatory sites may provide an attractive alternative to addressing NMDA receptor hypofunction.Activation of NMDA receptors requires the binding of both glutamate as an agonist and either glycine or D-serine as a coagonist. Recent clinical trials have shown beneficial effects of adjunctive D-serine and glycine treatment on both cognitive and negative symptom domains of schizophrenia (Javitt et al. 1994;Heresco-Levy et al. 1996 Abbreviations used: NMDA, N-methyl-D-aspartate; asc-1, Na + -independent alanine-serine-cysteine transporter 1; ASCT-1 and -2, Na + -dependent alanine-serine-cysteine transporter 1 and 2; LAT-1 and 2, large amino acid transporter; AIB, a-aminoisobutyric acid.

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mentioning

confidence: 97%

In vitro Characterization of a small molecule inhibitor of the alanine serine cysteine transporter ‐1 (SLC7A10)

Brown

Hunihan

Prack

et al. 2013

Journal of Neurochemistry

Self Cite

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Antipsychotic Agents

Cited by 1 publication

References 267 publications

In vitro Characterization of a small molecule inhibitor of the alanine serine cysteine transporter ‐1 (SLC7A10)

In vitro Characterization of a small molecule inhibitor of the alanine serine cysteine transporter ‐1 (SLC7A10)

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