Anti-inflammatory SSTR2 ligands
Royall, Sophie C. (2012) Anti-inflammatory SSTR2 ligands. PhD thesis, University of Warwick.
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Broad-Spectrum Chemokine Inhibitors (BSCIs) are a novel type of anti-inflammatory drug, discovered by Fox and colleagues, which act through the receptor SSTR2. Chapter 1 consists of the story of the development of current BSCIs and a literature review of existing SSTR2 ligands.
In Chapter 2 a series of receptor probes were synthesised based on existing SSTR2 ligands, BSCIs and a hybrid of the two. Biological data were gained determining their SSTR2 binding ability and their extent of leukocyte migration inhibition.
In Chapter 3 a series of small molecules were synthesised based on the structure of highly potent BSCIs. Once again biological data were gained determining their SSTR2 binding ability and their extent of leukocyte migration inhibition.
In Chapter 4 a series of BSCIs were synthesised which contained substituted aromatic groups using an iron-cross coupling reaction. Biological data were gained to determine these compounds SSTR2 binding ability. Further iron cross-coupling reactions were carried out to determine the scope of these reactions and their applications in medicinal synthetic chemistry.
This works has gained evidence to support a split binding site theory for SSTR2. Somatostatin and BSCIs bind in slightly different area of the binding site, and through functional selectivity somatostatin structural analogues can exert an anti-inflammatory effect while somatostatin does not.
|Item Type:||Thesis or Dissertation (PhD)|
|Subjects:||Q Science > QD Chemistry
R Medicine > RM Therapeutics. Pharmacology
|Library of Congress Subject Headings (LCSH):||Chemokines, Anti-inflammatory agents, Ligand binding (Biochemistry)|
|Official Date:||February 2012|
|Institution:||University of Warwick|
|Theses Department:||Department of Chemistry|
|Sponsors:||Engineering and Physical Sciences Research Council (EPSRC) ; University of Warwick. Molecular Organisation and Assembly in Cells ; Funxional Therapeutics Ltd.|
|Extent:||xx, 307 leaves : illustrations, charts|
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