Allosteric Modulation of the Mu Opioid Receptor.

[摘要] The mu opioid receptor (MOPr), a G protein-coupled receptor (GPCR), is the pharmacological site of action of morphine and related opioid narcotic agonists that bind to the orthosteric site on MOPr, evolutionarily developed to accommodate the endogenous opioid peptides.MOPr activation results in analgesia but also causes a number of unwanted effects including constipation, respiratory depression, tolerance, and euphoria leading to a high addictive liability. In contrast, small molecule positive allosteric modulators of MOPr (MOPr-PAMs) bind to alternative sites on the protein to modulate receptor function. MOPr PAMs represent a potential avenue for pain relief with a better therapeutic profile. Studies described in this thesis seek to understand the mechanism of action of MOPr PAMs. The results show that MOPr-PAMs promote an active state of MOPr by disruption of the Na+ binding site on the receptor, a mechanism that may be applicable to other GPCRs. Furthermore,this active state can be captured and measured by the camelid antibody Nb39 providing a novel method for quantifying orthosteric and allosteric agonist efficacy.The work also demonstrates that the allosteric site on MOPr can accommodate structurally diverse ligands, and is somewhat conserved on the related delta opioid receptor.Lastly, this thesis explores the effects of chronic allosteric enhancement of MOPr signaling on the downstream processes of receptor desensitization and cellular tolerance in vitro.

[发布机构] University of Michigan

[效力级别] Opioid Pharmacology

[关键词] GPCR;Opioid Pharmacology;Allostery;Efficacy;Science;Pharmacology