Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.772361
Title: Design and synthesis of fluorescent opioids for bioimaging
Author: Lam, Raymond
ISNI:       0000 0004 7959 8497
Awarding Body: Monash University, University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2018
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Abstract:
Opioids are a class of alkaloid that have been used since pre-history for the treatment and control of pain. Morphine and codeine, the active ingredients in the opium latex from the plant Papaver somniferum, have been known since the 19th century. Although their use in the clinic is widespread, they suffer from various adverse effects, including euphoria, constipation, respiratory depression, tolerance, dependence. These last two side effects are of note, as they are responsible for increasing opioid addiction and related deaths in the United States, as well as in other parts of the world. These drugs act at the mu-opioid receptor (MOR), a G protein-coupled receptor (GPCR) thought to be the primary target of all opioid analgesics. Classically, it was viewed that GPCRs acted as single units, with an active and inactive state. This simplistic view of GPCR activation fails to explain the varying pharmacological profiles of different opioid drugs. More recently, a new paradigm has emerged in which GPCRs may act as heterodimers, forming functional units with different GPCRs. The MOR has been demonstrated to form heterodimers with various receptors. These include the δ-opioid receptor (DOR), the neurokinin 1 receptor and the cannabinoid 1 receptor just to name a few. Knock-out animal models demonstrate the therapeutic possibilities of targeting these heterodimers. Studying the MOR has historically been hindered by a lack of useful tool compounds. Previous attempts utilized peptide agonists conjugated to fluorescent tags. Attempts at producing small molecule probes have typically resulted in antagonists, and therefore there is a need to develop novel small molecule opioid agonist probes for the MOR. Furthermore, there is a need to develop new systems in order to study GPCR heterodimers. Of particular interest here is the MOR-DOR heterodimer, as various literature has shown the therapeutic potential of this dimer. For this purpose, we envisioned a nanoparticle-based system to allow for conjugation of multiple congeners to produce a multidentate system. During the synthesis of these probes, the N-demethylation of alkaloids was of particular importance. Opioids, like many other alkaloids, contain N-methyl moieties. Replacement of ABSTRACT XIV this methyl group allows for attachment of other alkyl groups that may give varying and clinically useful pharmacologies. Several historical methods are available, including the von Braun reaction, the Polonovski reaction and the use of chloroformates. These all suffer from various drawbacks that limit their use. The more recent development of a non-classical Polonovski reaction enables direct access to the N-nor product from the N-oxide, which is advantageous compared to the historical methods. These reactions utilize various iron species, from iron salts to organometallic complexes. During this is work, new conditions for the non-classical Polonovski reaction were found and optimized. Here, we explored the use of Fe3(CO)12, a metallo-carbonyl complex that has previously not been described as a catalyst. In addition, we explored the effect of its catalytic activity in various solvents, as well as on a variety of biologically interesting alkaloids.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.772361  DOI: Not available
Keywords: QP Physiology
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