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.
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.
|Elgarf, Alshaimaa A; Siebert, David C B; Steudle, Friederike et al. (2018) Different Benzodiazepines Bind with Distinct Binding Modes to GABAA Receptors. ACS Chem Biol 13:2033-2039|
|Chiou, Lih-Chu; Lee, Hsin-Jung; Ernst, Margot et al. (2018) Cerebellar ?6 -subunit-containing GABAA receptors: a novel therapeutic target for disrupted prepulse inhibition in neuropsychiatric disorders. Br J Pharmacol 175:2414-2427|
|McMurray, K M J; Ramaker, M J; Barkley-Levenson, A M et al. (2018) Identification of a novel, fast-acting GABAergic antidepressant. Mol Psychiatry 23:384-391|
|Fan, Pi-Chuan; Lai, Tzu-Hsuan; Hor, Chia Chun et al. (2018) The ?6 subunit-containing GABAA receptor: A novel drug target for inhibition of trigeminal activation. Neuropharmacology 140:1-13|
|Heise, Christopher; Taha, Elham; Murru, Luca et al. (2017) eEF2K/eEF2 Pathway Controls the Excitation/Inhibition Balance and Susceptibility to Epileptic Seizures. Cereb Cortex 27:2226-2248|
|Stephen, Michael Rajesh; Rahman, M Toufiqur; Tiruveedhula, V V N Phani Babu et al. (2017) Concise Total Synthesis of (-)-Affinisine Oxindole, (+)-Isoalstonisine, (+)-Alstofoline, (-)-Macrogentine, (+)-Na -Demethylalstonisine, (-)-Alstonoxine?A, and (+)-Alstonisine. Chemistry 23:15805-15819|
|Witkin, J M; Cerne, R; Wakulchik, M et al. (2017) Further evaluation of the potential anxiolytic activity of imidazo[1,5-a][1,4]diazepin agents selective for ?2/3-containing GABAA receptors. Pharmacol Biochem Behav 157:35-40|
|Schwienteck, Kathryn L; Li, Guanguan; Poe, Michael M et al. (2017) Abuse-related effects of subtype-selective GABAAreceptor positive allosteric modulators in an assay of intracranial self-stimulation in rats. Psychopharmacology (Berl) 234:2091-2101|
|Forkuo, Gloria S; Nieman, Amanda N; Yuan, Nina Y et al. (2017) Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABAA Receptor Modulators. Mol Pharm 14:2088-2098|
|Jahan, Rajwana; Stephen, Michael Rajesh; Forkuo, Gloria S et al. (2017) Optimization of substituted imidazobenzodiazepines as novel asthma treatments. Eur J Med Chem 126:550-560|
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