Efficacy at the Mu Opioid Receptor

Efficacy at the Mu Opioid Receptor: Insights from Orthosteric and Allosteric Ligands – Federation of American Societies for Experimental Biology

The mu opioid receptor (MOPr) represents one of the most pharmacologically targeted G protein-coupled receptors (GPCRs) worldwide.

Activation by an orthosteric agonist like morphine causes robust pain relief but also results in unwanted effects including respiratory depression, constipation, and addiction liability.

However, these actions have different agonist efficacy requirements. Consequently an understanding of the factors governing efficacy is required. 

In addition, we have recently described a series of positive allosteric modulators (PAMs), exemplified by the thiazolidine BMS-986122 that control the affinity and/or efficacy of orthosteric MOPr ligands.

Here we report that BMS-986187, a delta opioid receptor (DOPr) PAM, although structurally very distinct from BMS-986122 acts as a MOPr-PAM with increased allosteric efficacy compared to BMS-986122, but with the same probe dependence and the same mechanism of action: by allosterically disrupting Na+ binding.

Furthermore, competition experiments suggest that BMS-986187 binds to the same site as BMS-986122 indicating a somewhat conserved allosteric binding site on MOPr and DOPr.

Utilizing purified MOPr reconstituted into high density lipoprotein (HDL) particles we have studied binding of the MOPr state-sensitive sensor nanobody39 (Nb39) by interferometry to monitor formation of MOPr active state.

Differences in orthosteric ligand efficacy were seen to correlate with different kinetics of Nb39 association and dissociation.

The PAMs alone enhanced the on-rates of Nb39 but differences were seen reflective of distinct allosteric efficacies. Finally, we show that cooperativity between agonist and BMS-986187 is unchanged in the absence or presence of G proteins suggesting that the allosteric modulators alone are able to stabilize of an active state of MOPr.


This abstract is from the Experimental Biology 2016 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.  

Other thoughts?

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s