Novel GPCR paradigms at the μ‐opioid receptor

Abstract

Opioids, such as morphine, are the most clinically useful class of analgesic drugs for the treatment of acute and chronic pain. However, the use of opioids is greatly limited by the development of severe adverse side effects. Consequently, drug discovery efforts have been directed towards improving the therapeutic profile of opioid-based treatments. Opioid receptors are members of the family of GPCRs. As such, the recent GPCR paradigms of biased agonism and allosterism may provide novel avenues for more effective analgesics. Biased agonism (or functional selectivity) has been described for all the opioid receptor family members. Furthermore, the first allosteric modulators of opioid receptors have very recently been described. However, identification and quantification of biased agonism in a manner that is informative to medicinal chemists and drug discovery programmes still remains a challenge. In this review, we examine the progress, to date, towards identification and quantification of biased agonism and allosterism at the μ-opioid receptor in the context of its implications for the discovery of better and safer analgesics. LINKED ARTICLESThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx

Biased Agonism of Endogenous Opioid Peptides at theμ-Opioid Receptor

“…This is similar to results obtained by Rivero et al (2012), where morphine was slightly biased toward b-arr2, although not significantly (Thompson et al, 2015).…”

“…35 S]GTPgS binding and b-arr2 recruitment in HEK293 cells for some endogenous ligands, and found that endo-1 and endo-2 were biased toward b-arr2 recruitment compared with leu-enkephalin (McPherson et al, 2010;Rivero et al, 2012;Thompson et al, 2015). In our study, only endo-1 was biased toward b-arr2 over […”

“…First, the different methodologies and time points used to measure b-arr2 recruitment may affect bias, since at later time points differential rates and modes of desensitization may affect the level of b-arr2 recruitment. In addition, the different cell backgrounds used in each study may also change the bias of a ligand, as the expression levels of the various proteins involved in the activation of the Endogenous Biased Agonism at the m-Opioid Receptor signaling pathways examined may differ across cell lines and have an impact in the measures of bias (Thompson et al, 2015).…”

“…Biased agonism at the MOP has been extensively studied (McPherson et al, 2010;Al-Hasani and Bruchas, 2011;Raehal et al, 2011;Pradhan et al, 2012;Rivero et al, 2012;Kelly, 2013;Williams et al, 2013;Thompson et al, 2015). However, evidence of biased agonism at the MOP is mostly limited to qualitative analyses of two signaling events with a limited number of ligands.…”

“…Recently, ligands with impaired b-arr2 recruitment have been reported to provide potent analgesia with less severe side effects (Groer et al, 2007;DeWire et al, 2013;Soergel et al, 2014). However, the improved pharmacological profiles of these ligands may still be due to their partial agonism, with lower overall efficacy than morphine, rather than true "bias" away from b-arr2 recruitment (Thompson et al, 2015).…”