All clinical opioid analgesics target the MOP (Mu Opioid Peptide) receptor. While these drugs provide analgesia, long-term treatment leads to tolerance and dependence. By targeting MOP and another member of the opioid receptor family, such as DOP (Delta Opioid Peptide receptor) or NOP (Nociceptin Orphanin F/Q Opioid Peptide receptor), these adverse effects are attenuated. Furthermore, solely targeting DOP or NOP may produce analgesia without the adverse effects associated with MOP. Three groups of variably mixed ligands have been developed; i) Fentanyl-based DOP and NOP bivalents, ii) peptide based MOP and NOP bivalents iii) tetrabranched NOP and DOP monovalent ligands. The pharmacology of these ligands has been investigated in a range of intracellular signalling assays. All compounds were tested in Chinese hamster ovary (CHO) cells expressing human MOP, NOP, DOP or KOP (Kappa Opioid Peptide receptor) receptors. Initial work with Fentanyl-based DOP bivalents resulted in a loss of functional activity at the MOP receptor. Further Fentanyl-derivatives conjugated with Ro65-6570 displayed partial agonist activity at MOP and full agonist activity at MOP. A second MOP/NOP bivalent pharmacophore, (DeNO), based on the peptides Dermorphin (MOP) and N/OFQ demonstrated full agonist activity at both receptors. A tetrabranched ligand formed from N/OFQ, displayed increased potency at the NOP receptor compared to N/OFQ. DeNO was investigated in human embryo kidney (HEK) cells which co-expressed MOP and NOP. The results of functional assays demonstrated a loss of MOP activity caused by the presence of NOP. Further studies with the opioids, Dermorphin and N/OFQ, and antagonists naloxone (MOP) and UFP-101(NOP), have demonstrated a structural interaction between MOP and NOP in this cell line. The work in this thesis demonstrates how modification of peptide structures was more successful in the development of multitarget ligands. The findings from this thesis provide a significant contribution to theory of receptor heterodimerisation between MOP and NOP, as demonstrated by the loss of potency of MOP agonists in the co-expression system.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:713344 |
| Date | January 2015 |
| Creators | Bird, Mark Francis |
| Contributors | Lambert, David G. ; Rowbotham, David J. |
| Publisher | University of Leicester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/2381/39639 |
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