Optimizing Lead 5-HT2c Ligands for Use in the Treatment of Schizophrenia

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DESCRIPTION (provided by applicant): 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.