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dc.contributor.advisorVernall, Andrea
dc.contributor.advisorHook, Sarah
dc.contributor.advisorTyndall, Joel
dc.contributor.authorCooper, Anna Gabrielle
dc.date.available2018-04-05T04:12:20Z
dc.date.copyright2018
dc.identifier.citationCooper, A. G. (2018). Development of Fluorescent Ligands for CB2 receptor (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/7991en
dc.identifier.urihttp://hdl.handle.net/10523/7991
dc.description.abstractCB2 receptor plays an important role in inflammation and has been implicated in the pathologies of several diseases, including neurodegenerative disorders, cancer, and atherosclerosis. However, there is a lack of understanding of CB2 receptor expression and signalling, which significantly hinders the development of CB2 receptor-targeted therapies. The availability of a diverse range of advanced pharmacological tools for studying CB2 receptor would lead to improved understanding of CB2 receptor and thus aid drug development. Fluorescent ligands have been developed for other GPCRs and used to elucidate receptor expression and signalling roles. The aim of this PhD research was to develop a fluorescent ligand with high affinity and selectivity for CB2 receptor which would be suitable for use as a pharmacological tool. The alkylindole class of cannabinoids are well characterised regarding CB2 receptor affinity, selectivity and function, which was used to guide design of a series of fluorescent ligands. Compounds with linker and fluorophore substitution at the C5-, C6- or C7 indole positions were designed, synthesised and pharmacologically evaluated for CB2 receptor affinity and function (Chapters Two and Three). No high affinity fluorescent ligands resulted from these alkylindole series, but a very high affinity, selective CB2 receptor inverse agonist 3.7b was identified amongst the non-fluorescent ligands. Alkylindole 3.7b showed very promising properties in relation to other small ligand inverse agonists for CB2 receptor. In addition, a lead pharmacophore-linker conjugate 3.13 was identified, which has potential for development into a fluorescent ligand. Fluorescent ligands were also developed from the 1,8-naphthyridin-2(1H)-one-3- carboxamide scaffold (Chapters Four and Five). A fluorescent ligand 5.9b with high affinity and selectivity for CB2 receptor (Ki = 467 ± 20.0 nM at hCB2 receptor, Ki = >10 μM at hCB1 receptor) was identified amongst these compounds. This fluorescent ligand (5.9b) has potential as a pharmacological imaging tool with which to study CB2 receptor and could also be further derivatised and optimised in the development of other fluorescent ligands for CB2 receptor with a range of properties. CB2 receptor homology models were generated and used in ligand docking studies to aid ligand design and to rationalise biological results.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectCB2 receptor
dc.subjectcannabinoid type 2 receptor
dc.subjectFluorescent ligand
dc.subjectalkylindole
dc.subjectChemical tools
dc.subjectGPCRs
dc.subjectcannabinoid
dc.subjectfluorescent probe
dc.subjectCB2
dc.titleDevelopment of Fluorescent Ligands for CB2 receptor
dc.typeThesis
dc.date.updated2018-04-05T03:12:41Z
dc.language.rfc3066en
thesis.degree.disciplinePharmacy
thesis.degree.nameDoctor of Philosophy
thesis.degree.grantorUniversity of Otago
thesis.degree.levelDoctoral
otago.openaccessOpen
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