G protein-coupled receptors (GPCRs) are seven-transmembrane domain receptors that sense extracellular signal and activate intracellular signaling pathways. The serotonin 5HT2A receptor (or 2AR) is one of the GPCRs coupled to Gq proteins, activating PLC and hydrolyzing PIP2. This hydrolysis causes a diffusion of bound PIP2 away from the channel binding site resulting in G protein-gated inwardly rectifying K+ channel (GIRK) inhibition and a downstream stimulation of Ca2+ release from endoplasmic reticulum stores. Previous experiments have demonstrated that the serotonin 5HTA receptor is a target of serotonergic psychedelic drugs, such as LSD, and partially mediates the action of many atypical antipsychotic drugs. However, the portion responsible for the functional activity and response of these drugs is unknown. The purpose of this study was to functionally characterize four deconstructed analogs of risperidone, an atypical antipsychotic agent, using two assays: by application to 5HT2A receptors in Xenopus oocytes and by calcium epifluorescence imaging in a HEK293 cell line stably expressing 2AR. Our experiments revealed that two analogs, RHV-006 and RHV-008, are partial agonists by themselves and greatly antagonize the effects of serotonin. RHV-006 and RHV-008 contain the piperidine and benzisoxizole ring systems of risperidone. RHV-023 and RHV-026, on the other hand, are more efficacious agonists than RHV-006 and RHV-008 but display a non-antagonistic effect with serotonin. RHV-023 and RHV-026 contain both the piperidine and benzisoxizole ring systems in addition to part of the diazabicyclo ring, thus containing more of risperidone’s structure than RHV-006 and RHV-008.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-4867 |
| Date | 01 January 2015 |
| Creators | Shah, Sneha |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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