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Title: Studies on the structure and function of the 5-HT1B receptor
Author: Bell, J. C.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2011
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In Chapter 1 a review of the 5-HT1B receptor is conducted, describing physiological and pathological roles as well as known ligands. The structural biology of Family A GPCRs is reviewed to provide insights into the behaviour of 5-HT1B itself. In Chapter 2, a multiple sequence alignment is used to study residue conservation in human monoamine GPCRs and to elucidate areas of functional and structural significance. Patterns are identified that are consistent with current knowledge of GPCR function while also producing novel insights into 5-HT1B receptor structure. In Chapter 3, homology modelling based upon both bovine rhodopsin and the human β2-adrenergic receptor is employed to construct models of 5-HT1B. In Chapter 4, molecular dynamics is then used to refine these structures, verify the intramolecular interactions identified in Chapter 2 and investigate conformation changes during receptor activation. In Chapter 5, existing ligands are studied and novel pharmacophores for the receptor are derived. Higher ligand recall with tighter constraints is achieved by introducing virtual sits into the pharmacophores. These pharmacophores are then integrated into the receptor models to compare them, to identify binding interactions and to investigate the dynamic behaviour of pharmacophores. From the conjunction of ligand and receptor-derived information a model for ligand efficacy is derived. In Chapter 6, the design of a novel series of 5-HT1b antagonists using and verifying the previously-derived models is described.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available