Phase II year
2009
(last award dollars: 2014)
Phase II Amount
$2,050,489
Schizophrenia is a debilitating disorder that affects almost 1% of the world's population. The burden on the families and caregivers of patients is immense, and the cost of care in the U.S. is >$60 billion/y. The high costs arise, in part, due to a lack of innovation that has resulted in very limited, ineffective treatments that are associated with poor compliance. Virtually all of the major antipsychotics approved by the FDA in the past fifty years act primarily on dopamine and/or serotonin receptor function, and unfortunately, these antipsychotics produce severe side effects and are ineffective in treating a number of the symptoms of schizophrenia. The overall goal of this Phase I SBIR is to capitalize on recent advances from the principal investigators laboratories implicating a highly novel mechanism of glutamate release that may contribute to schizophrenia. Specifically, cystine-glutamate exchange appears to be altered in schizophrenic patients, and targeting this mechanism has been shown to be highly effective in a rodent model of schizophrenia. In an effort to test the hypothesis that cystine-glutamate exchange represents an effective treatment target for schizophrenia and other disorders, we will synthesize novel cysteine analogs. Next, we will evaluate the capacity of the new analogs to induce cystine-glutamate exchange in cortical cultures in vitro, and test the most promising compounds for their ability to normalize sensorimotor gating deficits produced by phencyclidine in a rodent model of schizophrenia. The ability to identify therapeutic candidates by this approach will provide addition support for our hypothesis, and establish a basis for pursuing additional pre-clinical and ultimately clinical studies of cystine analogs as treatments for schizophrenia and potentially other psychiatric disorders.
Public Health Relevance: Schizophrenia is a debilitating disorder that results in a devastating burden on the families and caregivers of patients and a cost of care in the U.S. of >$60 billion/year. The high costs arise, in part, due to a lack of innovation that has resulted in very limited, ineffective treatments that are associated with poor compliance due to poor efficacy and the emergence of serious side effects. The primary goal of this Phase I SBIR is to develop novel treatments for schizophrenia.
Thesaurus Terms: 1-(1-Phenylcyclohexyl)Piperidine; 3,4-Dihydroxyphenethylamine; 4-(2-Aminoethyl)-1,2-Benzenediol; 5-Ht Receptors; 5-Hydroxytryptamine Receptors; Acetylcysteine; Acetylin; Address; Adverse Effects; Affect; Airbron; Allen & Hanburys Brand Of Acetylcysteine; Aminoacetic Acid; Angel Dust; Antipsychotic Agents; Antipsychotic Drugs; Antipsychotics; Automobile Driving; Blood - Brain Barrier Anatomy; Blood-Brain Barrier; Bristol-Myers Squibb Brand Of Acetylcysteine; Bristol-Myers Squibb Brand Of Acetylcysteine Sodium Salt; Broncholysin; Brunac; Caring; Cell Communication And Signaling; Cell Membrane Lipids; Cell Signaling; Clinical Research; Clinical Study; Cyst; Cysteine; Cystine; Data; Development; Diffusion; Disease; Disorder; Dopamine; Drivings, Automobile; Drug Precursors; Drugs; Dysfunction; Evaluation; Exhibits; Fda Approved; Fabrol; Family Care Giver; Family Caregiver; Fluatox; Fluimucetin; Fluimucil; Fluprowit; Functional Disorder; Glutamates; Glycine; Goals; Government; Half-Cystine; Hemato-Encephalic Barrier; Human; Human, General; Hydroxytyramine; In Vitro; Inpharzam Brand Of Acetylcysteine; Intermediary Metabolism; Intracellular Communication And Signaling; L-Alpha-Acetamido-Beta-Mercaptopropionic Acid; L-Cysteine; L-Cystine; L-Glutamate; Laboratories; Metbl; Major Tranquilizers; Mammals, Rodents; Man (Taxonomy); Man, Modern; Medication; Membrane Lipids; Mental Disorders; Mental Health Disorders; Mercapturic Acid; Metabolic Processes; Metabolism; Molecular; Muco Sanigen; Mucocedyl; Mucolator; Mucolyticum; Mucomyst; Mucosolvin; Mucret; N Methyl D Aspartic Acid; N Methyl D Aspartate; N-Acetyl Cysteine; N-Acetyl-L-Cysteine; N-Acetylcysteine; N-Methyl-D-Aspartate Receptors; N-Methyl-D-Aspartate; N-Methylaspartate; N-Acetyl-3-Mercaptoalanine; Nac; Nac Zambon; Nmda; Nmda Receptor-Ionophore Complex; Nmda Receptors; Nmda Receptor Antagonist; Neo-Fluimucil; Nerve Impulse Transmission; Nerve Transmission; Neural Development; Neuroleptic Agents; Neuroleptic Drugs; Neuroleptics; Neuronal Transmission; Optipect Hustengetr??Nk; Parvolex; Patients; Persons; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Phencyclidine; Physiopathology; Population; Prefrontal Cortex; Principal Investigator; Pro-Drugs; Process; Prodrugs; Produpharm Lappe Brand Of Acetylcysteine; Property; Property, Loinc Axis 2; Psychiatric Disease; Psychiatric Disorder; Receptors, N-Methylaspartate; Respaire; Roberts Brand Of Acetylcysteine; Rodent; Rodent Model; Rodentia; Rodentias; Sbir; Sbirs (R43/44); Schizophrenia; Schizophrenic Disorders; Screening Procedure; Signal Transduction; Signal Transduction Systems; Signaling; Site; Small Business Innovation Research; Small Business Innovation Research Grant; Source; Symptoms; Synapses; Synaptic; System; System, Loinc Axis 4; Testing; Therapeutic; Thiemann Brand Of Acetylcysteine; Tixair; Tranquilizing Agents, Major; Transmission; Treatment Side Effects; Upsa Brand Of Acetylcysteine; Unspecified Mental Disorder; Zambon Brand Of Acetylcysteine; Zyma Brand Of Acetylcysteine; Analog; Antiporter; Base; Biological Signal Transduction; Clinical Efficacy; Cost; Dementia Praecox; Design; Designing; Disease/Disorder; Driving; Drug/Agent; Effective Therapy; Experiment; Experimental Research; Experimental Study; Extracellular; In Vitro Testing; Innovate; Innovation; Innovative; Lipophilicity; Mental Illness; Neurodevelopment; Neurotransmission; Neurotransmitter Release; New Approaches; Novel; Novel Approaches; Novel Strategies; Novel Strategy; Passive Transport; Pathophysiology; Pre-Clinical; Preclinical; Prepulse Inhibition; Psychological Disorder; Public Health Relevance; Receptor Function; Research Study; Schizophrenic; Screening; Screenings; Serotonin Receptor; Side Effect; Therapeutic Target; Therapy Adverse Effect; Transmission Process; Treatment Adverse Effect
