Design, Synthesis, and Pharmacological Characterization of Serotonin (5-HT) 5-HT2C Receptor (5-HT2CR) Positive Allosteric Modulators
| dc.creator | Wild, Christopher Timothy | |
| dc.date.accessioned | 2021-04-21T15:48:24Z | |
| dc.date.created | 2018-05 | |
| dc.date.submitted | May 2018 | |
| dc.date.updated | 2021-04-21T15:48:25Z | |
| dc.description.abstract | A decreased signaling capacity at the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) regulates neurobehavioral processes that may underlie chronic health issues such as impulsivity disorders, drug addiction, depression, schizophrenia, and obesity. Therefore, restoration of the diminished signaling capacity through 5-HT2CR activation has therapeutic potential. A series of new molecules based on the 4-alkylpiperidine-2- carboxamide scaffold and oleamide were designed, synthesized, and pharmacologically evaluated as 5-HT2CR positive allosteric modulators (PAMs). Several analogues potentiated intracellular calcium release by 5-HT in h5-HT2CR-CHO cells. Several compounds exhibited a favorable overall pharmacokinetic profile and modulated 5-HT2CRassociated behaviors (e.g., spontaneous motor activity and drug discrimination) in rats. Two predicted allosteric sites were identified by molecular docking to a 5-HT2CR homology model. Taken together, these data represent the only combination of in vitro and in vivo evidence of a synthetic small molecule acting as a 5-HT2CR PAM providing a proof of concept that allosteric modulation of 5-HT2CR is a viable strategy toward the discovery of novel neurotherapeutics. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | https://hdl.handle.net/2152.3/11275 | |
| dc.subject | serotonin, positive allosteric modulator | |
| dc.title | Design, Synthesis, and Pharmacological Characterization of Serotonin (5-HT) 5-HT2C Receptor (5-HT2CR) Positive Allosteric Modulators | |
| dc.type | Thesis | |
| dc.type.material | text | |
| local.embargo.lift | 2021-05-01 | |
| local.embargo.terms | 2021-05-01 | |
| thesis.degree.department | Pharmacology and Toxicology | |
| thesis.degree.grantor | The University of Texas Medical Branch at Galveston | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Pharmacology and Toxicology (Doctoral) |