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Title: Allosteric modulation of the cannabinoid receptors
Author: Baillie, Gemma
ISNI:       0000 0004 2672 5018
Awarding Body: Aberdeen University
Current Institution: University of Aberdeen
Date of Award: 2008
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During this study the [35S]GTPγS binding, equilibrium binding and dissociation kinetic assays were utilised to investigate allosteric modulation of the cannabinoid receptors. ORG27569 and ORG29647, two allosteric modulators of the cannabinoid CB1 receptor, were shown to act as allosteric inhibitors of signalling efficacy.  They also displayed a ligand dependent effect on a range of CB1 receptor agonists. Using the [35S]GTPγS binding assay and HEK293 hCB1 wild-type cells, ORG27569 was shown to have inverse agonist properties for the first time. The location of the allosteric binding site was investigated using transfected CB1 receptor HEK293 cells each with a mutation of a single amino acid residue.  A specific amino acid residue in the CB1 receptor sequence was found to be vital in the binding and signalling on the allosteric modulator ORG27569.  A mutation of the amino acid residue W5.43 resulted in a complete loss in the ability of ORG2756 to allosterically inhibit CP55940. Further investigation into the allosteric binding site on the CB1 receptor led to the development of 11 novel compounds.  Each structural alteration helped to further understand the binding site and led to the development of MOST016.  MOST016 is a potent and efficacious allosteric modulator similar to ORG27569 and helped to determine a possible location on the CB1 receptor for the allosteric binding site. The compounds F0870063 and F0870064 which have no resemblance to the Organon compounds were investigated and discovered as the first allosteric enhancers of the cannabinoid CB1 receptor.  Both compounds slowed the dissociation rate of CP55940 from mouse brain membranes in the dissociation kinetic assays as well as enhancing agonist stimulation in the [35S]GTPγS binding assay. Finally, using the dissociation kinetic assay preliminary evidence for an allosteric binding site on the cannabinoid CB2 receptor was discovered in this study.  The most potent allosteric inhibitor of agonist binding affinity of the cannabinoid CB2 receptor was Δ9-THCV.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available