DMXB-A is a prototypic selective alpha7 nicotinic receptor agonist that has been tested extensively both preclinically and in Phasel and 2 clinical tests in schizophrenia. This compound is a weak partial agonist with relatively short plasma half-life. It has been shown to enhance various measures of cognition including increases in attention and sensory gating. The purpose of this Core project is to synthesize DMXB-A in sufficient amounts and purity for further clinical and pre-clinical tests. The FDA has stipulated that the synthetic DMXB-A display a chemical purity equivalent to a commercial product made under Good Manufacturing Practice (GMP) standards. This will require most of the requested effort of the synthetic chemist for Year 1 of the project. A second function of this Core will be to measure plasma samples from animals and humans that have been administered DMXB-A to determine its concentration and those of its active metabolites. This will be done according to previously reported HPLC protocols that allow concurrent measurement of parent compound and its 4-OH, 2-OH, and 2,4-Dihydroxy metabolites. These metabolites are potent full agonists and may be involved in the neurobiological response to DMXB-A administration. These data will allow tests of correlation between clinical effect and plasma drug levels. The final function of the Core will be to identify and synthetically provide additional related compounds for clinical tests. Core C provides clinical research support to Project 1 and basic research support to Projects 4, 5, and 6.

Public Health Relevance

New therapeutic strategies for schizophrenia are needed to improve cognitive dysfunction and negative symptoms and to prevent the development of psychosis. The Center investigates a nicotinic acetylcholine receptor as a new therapeutic target. Investigational results are used to design a new drug treatment for schizophrenia and a preventative nutrient intervention during infant development, both of which activate this r(=^r.e^rifnr

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
1P50MH086383-01
Application #
7752204
Study Section
Special Emphasis Panel (ZMH1-ERB-F (01))
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
1
Fiscal Year
2009
Total Cost
$130,564
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Hutchison, Amanda K; Hunter, Sharon K; Wagner, Brandie D et al. (2017) Diminished Infant P50 Sensory Gating Predicts Increased 40-Month-Old Attention, Anxiety/Depression, and Externalizing Symptoms. J Atten Disord 21:209-218
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Chow, Ke-Huan; Yan, Zihao; Wu, Wei-Li (2016) Induction of Maternal Immune Activation in Mice at Mid-gestation Stage with Viral Mimic Poly(I:C). J Vis Exp :e53643
D'Anna-Hernandez, Kimberly L; Garcia, Esmeralda; Coussons-Read, Mary et al. (2016) Sleep Moderates and Mediates the Relationship Between Acculturation and Depressive Symptoms in Pregnant Mexican-American Women. Matern Child Health J 20:422-33
Reed, Alexandra C; Harris, Josette G; Olincy, Ann (2016) Schizophrenia, smoking status, and performance on the matrics Cognitive Consensus Battery. Psychiatry Res 246:1-8
Ross, Randal G; Hunter, Sharon K; Hoffman, M Camille et al. (2016) Perinatal Phosphatidylcholine Supplementation and Early Childhood Behavior Problems: Evidence for CHRNA7 Moderation. Am J Psychiatry 173:509-16

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