Protein-Protein Interactions with Serotonin G Protein Coupled Receptors: Novel Targets for Neurotherapeutics Drug Discovery
Soto, Claudia Alejandra
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G protein coupled receptors (GPCRs) are involved in many physiological processes and are important therapeutic targets for a variety of human health disorders. In fact, approximately 30% of current FDA-approved medications target GPCRs and that number is likely to continue to rise with current GPCR-targeted drug discovery efforts. The main approach to pharmacologically manipulate GPCRs is to develop synthetic agonists, inverse agonists and antagonists that target the orthosteric site. While this approach has yielded several important medications, the development of selective orthosteric ligands is challenging and has led to the loss of many promising therapeutic candidates from the drug development pipeline due to adverse events attributed to off-target effects. Therefore, alternative strategies to develop GPCR drugs with enhanced selectivity are necessary. One alternative approach is to target GPCR protein-protein interactions (PPIs) that are selective for the GPCR of interest and involved in the regulation of the receptor function. This dissertation provides proof-of-concept data of two PPIs within the serotonin (5-HT) 5-HT2 receptor (i.e., 5-HT2CR and 5-HT2AR) system which may be promising targets for the treatment of neuropsychiatric disorders. The 5-HT2CR has been implicated in anxiety, binge eating disorder, depression, impulsivity, movement disorders, obesity, schizophrenia and substance use disorders and selective 5-HT2CR agonists display therapeutic potential. We show that disruption of the 5-HT2CR interaction with the protein phosphatase and tensin (PTEN) via peptide-based PPI disrupters enhance 5-HT2CR-mediating signaling in vitro and potentiates selective 5-HT2CR agonists in behavioral rodent models. On the other hand, antagonism of the 5-HT2AR is postulated to be a critical component in the actions of atypical antipsychotics (e.g., clozapine) and has been shown to improve symptomatology in preclinical models of psychostimulant addiction, anxiety, depression and sleep disorders. Here, we propose that targeting 5-HT2AR:5-HT2AR receptor-receptor interactions with bivalent ligands that have two pharmacophores that bind the orthosteric site tethered via a chemical linker provide potential therapeutically beneficial compounds. This dissertation provides initial characterization of 5-HT2AR:5-HT2AR homobivalent ligands that retain antagonism properties both in vitro and in vivo. Based on the cases explored here and other promising examples in the field, PPIs provide a much needed alternative approach for the selective regulation of GPCRs and should be considered, studied and exploited for their potential clinical implications.