Inflammatory bowel disease (IBD) is a serious, complex disease that is challenging to treat effectively and affects over 5 million people globally. Current treatment goals for both subtypes of IBD, Ulcerative Colitis (UC) and Crohn Disease (CD), focus on attaining and maintaining remission through anti-inflammatory agents, immunomodulators, or biologics. In spite of these treatments, more than 25% of patients require devastating surgical removal of part of their colon due to severe inflammation. Recent advances in our understanding of serotonergic effects beyond the central nervous system (CNS) provide encouragement for IBD treatment. The newest member of serotonin receptor family, the 5-HT7 subtype, is involved in the release of pro-inflammatory cytokines following stimulation by serotonin in the gastrointestinal tract (GIT). Khan et al have shown that inflammation associated with the DSS and DNBS mouse models of IBD is significantly attenuated in knock-out mice lacking the 5-HT7 receptor or mice treated with 5-HT7 selective antagonists. Previously reported 5-HT7 receptor antagonists (e.g., SB-269970) readily crosses the blood brain barrier (BBB) and are therefore not good choices for IBD treatments. Our group has identified a novel series of arylpiperazinyl lactones with high affinity and excellent selectivity for the 5-HT7. The aim of this project is to design, synthesize, and characterize new gamma-butyrolactone-based 5-HT7 ligands with high affinity, good selectively, acceptable drug-like properties, with limited access to the CNS. A total of 18 compounds were successfully synthesized and evaluated as potential new lead compounds for the treatment of IBD. / Pharmaceutical Sciences
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/1304 |
| Date | January 2018 |
| Creators | Giratallah, Haidy |
| Contributors | Canney, Daniel J., Blass, Benjamin E., Childers, Wayne E. |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 132 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/1286, Theses and Dissertations |
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