Our ultimate goal is to synthesize and characterize novel 5-HT2c serotonin agonists that may be useful for treating schizophrenia and related disorders. Our preliminary findings, as well as those of others, indicate that 5-HT2C agonists are effective in animal models predictive of efficacy against the positive and cognitive symptoms of schizophrenia. Because 5-HT2C agonists are not associated with the metabolic and motoric side- effects characteristic of current typical and atypical antipsychotic drugs, 5-HT2C agonists would afford novel treatment strategies for schizophrenia and related disorders. To achieve this overall goal we have three specific aims.
Aim 1 : To further expand and improve upon the potent 5-HT2c ligands that we have already identified using rational drug design principles and chemical intuition. Structural alterations will be made to enhance 5-HT2c subtype selectivity and to avoid any 5-HT2B valvuopathic-associated activity, while also improving upon compound solubility and ADMET parameters as needed to achieve the desired efficacy in preclinical animal studies.
Aim 2 : Characterize binding affinities and functional activities of putative 5-HT2c agonists for the human and mouse 5-HT2c-INI, 5-HT2c-NVN and 5-HT2c-VSV receptor-isoforms. We will also evaluate specificity of putative 5-HT2c agonists by assessing 5-HT2A and 5-HT2B receptor activities by radioligand binding and functional assays. The best compounds emerging from these studies will be subjected to a large battery of assays for identification of off-target activity.
Aim 3 : To evaluate the best 5-HT2c ligands identified in Specific Aims 1 and 2 in a battery of schizophrenia- related behavioral assays to test for antipsychotic efficacy and possible pro-cognitive effects. The behavioral studies will be conducted with pharmacological and genetic models of schizophrenia-like behaviors;5-HT2C- knockout mice will serve as controls. The strength of this proposal lies in: (1) Targeting a receptor for which there are no currently approved medications (i.e. a novel molecular target);(2) 5-HT2C agonists are likely to have clinical indications beyond schizophrenia including bipolar disorder, depression, obesity, and drug abuse (i.e. many potential clinical indications);(3) With respect to schizophrenia, two different 5-HT2C agonists have already shown efficacy in animal models predictive of efficacy for positive- and cognitive-like schizophrenia symptoms. Since cognitive symptoms are very difficult to treat in schizophrenia, the 5-HT2C compounds may represent a novel treatment strategy;(4) Finally, it is likely that 5-HT2C agonists will not only be devoid of the metabolic ad motoric side- effects associated with current medications but may also be beneficial from a metabolic perspective.

Public Health Relevance

5-HT2C agonists have demonstrated efficacy in preclinical models of depression, obesity, addiction, and psychosis. Targeting the 5-HT2C receptor thus appears to offer a promising means for developing novel therapeutics for treating many neuropsychiatric disorders. By combining medicinal chemistry with appropriate functional studies at the required 5-HT receptor subtypes, together with cutting edge pharmacological and genetic models of hyperdopaminergia and hypoglutamatergia in our assessments of schizophrenia-like behaviors in mice, the approach is likely to identify innovative drug candidates for the treatment of schizophrenia that show fewer side effects than current medications.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (DDNS)
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Driscoll, Jamie
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University of Illinois at Chicago
Schools of Pharmacy
United States
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