Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436643
Title: Molecular pharmacology of a novel NR2B-selective NMDA receptor antagonist
Author: Bradford, Andrea Marie
Awarding Body: Durham University
Current Institution: Durham University
Date of Award: 2006
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Abstract:
The NMDA receptor is a heteromeric ligand-gated ion channel in the central nervous system (CNS). There are three families of NMDA receptor subunits with various combinations of NRl, NR2A-D and NR3A֊B subunits producing unique receptors with distinctive pharmacological and biochemical properties. Pharmacological and functional properties of the NMDA receptor are highly dependent on the composition of the receptor complex. The NMDA receptor is the focus of drug development for therapy and prevention of numerous neurological and psychiatric disorders. The focus of this thesis was to investigate NMDA receptor subtype selectivity of NMDA antagonists, in particular, RGH-896, a novel NR2B֊selective antagonist. The study has utilised radioligand binding competition binding assays with RGH-896 in native, recombinant and immunopurified NMDA receptor preparations. In addition, ligand autoradiography has been employed to quantify and delineate the regional distribution of [^3H] RGH-896 binding sites in rodent and human brain tissue. This study provides the first evidence that [3H] RGH-896 binds to a distinct binding site which displays a significantly lower affinity for spermidine compared to the [^3H] Ro 25,6981 binding site. In addition, the low sensitivity of [^3H] MK-801 for unlabelled RGH-896 compared to prototypical NR2B ligand ifenprodil is further evidence for the difference in binding sites. Novel immunopurification studies using [3H] RGH-896, in contrast to [3H] CP 101,606, binds to NR2B-containing receptors irrespective of NMDA receptor subunit combinations. Ligand autoradiography in human brain has shown a surprising overall preservation of NR2B receptors in dementia with Lewy bodies (DLB) patients compared to age matched controls in the anterior cingulate cortex (ACC). However, this study has revealed the first evidence of an upregulation of NR2B receptors in ACC of DLB cases related to severity of auditory, but not visual hallucinations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.436643  DOI: Not available
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