Schizophrenia is a debilitating disorder that affects almost 1% of the world's population. The burden on the caregivers of patients is immense, and the cost of care in the U.S. is >$60 billion/y. Virtually all of the major antipsychotics approved y the FDA act primarily on dopamine and/or serotonin receptor function. Unfortunately, these antipsychotics produce serious side effects and are ineffective in treating negative symptoms and cognitive deficits of schizophrenia. Thus, there is an urgent need to develop treatments to alleviate these symptoms and deficits for schizophrenia patients preferably with novel drug candidates. Our long term goal is to generate compounds that are -subunit selective ligands of the GABAA receptors to determine the biological functions of different -subunits and to develop new therapies for human diseases. The objective here is to generate nonsedating agents for the treatment of negative symptoms and cognitive deficits of schizophrenia with little or no abuse potential (weak or no efficacy at 1 GABAA receptor subunits). Our central hypothesis is that selective modulators of the ?3,?5, or ligands with equal efficacy for the ?2,?3, and ?5 subunits (?2/?3/?5) bearing GABAA receptors, which have been shown to attenuate negative symptoms and cognitive deficits of schizophrenia in animal models of this disease, are potentially the first drug candidates to address these symptoms of schizophrenia. The rationale is that these drug candidates will be available for IND filing and clinical trials once the development of current lea compounds described in this application is successfully completed. The following four specific aims are proposed: 1) Determine the activity of selective GABAA receptor modulators in animal models of schizophrenia;2) Develop highly ?5 and ?2/?3/?5 selective GABAA receptor modulators;3) Develop highly 3 selective GABAA receptor modulators;and 4) Determine in vivo activity of highly subtype selective GABAA receptor modulators.
Under specific aim one two lead compounds successfully re- versed the increase of tonic DA transmission in MAM rats, which suggests that these compounds would be effective in alleviating DA-mediated psychosis. Additionally, behavioral sensitivity to psychostimulants was reduced, restoring the rhythmicity within HPC-efferent structure, which is expected to be important for the alleviation of cognitive and negative symptoms of schizophrenia. Additionally, these compounds were able to reverse the cognitive symptoms of schizophrenia in the PPI model of PCP treated rats but induced no signs of catalepsy.
Under specific aims 2 and 3, synthetic routes to generate the proposed compounds are already establish and under specific aims 4 nonsedating properties of lead compounds has been evaluated in different animal models including rhesus monkeys. The approach is innovative because it focuses on the development and application of chiral and -subtype selective imidazobenzodiazepines (IBZ) as new therapies for schizophrenia. The proposed work is significant because it represents the first step in a continuum of research to develop the first therapies for impaired cognitive function and negative symptoms of schizophrenia patients.

Public Health Relevance

The proposed research is relevant to public health because the development of alpha subtype selective GABAA receptor ligands is ultimately expected to increase our understanding of the central nervous system and enables the development of new drugs to treat mental disorders and diseases. The proposed research is relevant to the part of NIH's mission to apply fundamental knowledge to reduce the devastating burden on the families and caregivers of schizophrenia patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH096463-02
Application #
8642208
Study Section
Special Emphasis Panel (DDNS)
Program Officer
Driscoll, Jamie
Project Start
2013-04-15
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$371,529
Indirect Cost
$103,854
Name
University of Wisconsin Milwaukee
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
627906399
City
Milwaukee
State
WI
Country
United States
Zip Code
53201
Rae, Caroline D; Davidson, Joanne E; Maher, Anthony D et al. (2014) Ethanol, not detectably metabolized in brain, significantly reduces brain metabolism, probably via action at specific GABA(A) receptors and has measureable metabolic effects at very low concentrations. J Neurochem 129:304-14
McMurray, Katherine M J; Distler, Margaret G; Sidhu, Preetpal S et al. (2014) Glo1 inhibitors for neuropsychiatric and anti-epileptic drug development. Biochem Soc Trans 42:461-7
Gill, Kathryn M; Cook, James M; Poe, Michael M et al. (2014) Prior antipsychotic drug treatment prevents response to novel antipsychotic agent in the methylazoxymethanol acetate model of schizophrenia. Schizophr Bull 40:341-50
Sawyer, Eileen K; Moran, Casey; Sirbu, Madelynn H et al. (2014) Little evidence of a role for the *1GABAA subunit-containing receptor in a rhesus monkey model of alcohol drinking. Alcohol Clin Exp Res 38:1108-17
Sengupta, Soma; Weeraratne, Shyamal Dilhan; Sun, Hongyu et al. (2014) *5-GABAA receptors negatively regulate MYC-amplified medulloblastoma growth. Acta Neuropathol 127:593-603
Paul, Jolly; Yevenes, Gonzalo E; Benke, Dietmar et al. (2014) Antihyperalgesia by *2-GABAA receptors occurs via a genuine spinal action and does not involve supraspinal sites. Neuropsychopharmacology 39:477-87
Kova?evi?, Jovana; Timi?, Tamara; Tiruveedhula, Veera V et al. (2014) Duration of treatment and activation of ?1-containing GABAA receptors variably affect the level of anxiety and seizure susceptibility after diazepam withdrawal in rats. Brain Res Bull 104:1-6