Discovery of positive allosteric modulators and silent allosteric modulators of the μ-opioid receptor

Abstract

μ-Opioid receptors are among the most studied G protein-coupled receptors because of the therapeutic value of agonists, such as morphine, that are used to treat chronic pain. However, these drugs have significant side effects, such as respiratory suppression, constipation, allodynia, tolerance, and dependence, as well as abuse potential. Efforts to fine tune pain control while alleviating the side effects of drugs, both physiological and psychological, have led to the development of a wide variety of structurally diverse agonist ligands for the μ-opioid receptor, as well as compounds that target κ- and δ-opioid receptors. In recent years, the identification of allosteric ligands for some G protein-coupled receptors has provided breakthroughs in obtaining receptor subtype-selectivity that can reduce the overall side effect profiles of a potential drug. However, positive allosteric modulators (PAMs) can also have the specific advantage of only modulating the activity of the receptor when the orthosteric agonist occupies the receptor, thus maintaining spatial and temporal control of receptor signaling in vivo. This second advantage of allosteric modulators may yield breakthroughs in opioid receptor research and could lead to drugs with improved side-effect profiles or fewer tolerance and dependence issues compared with orthosteric opioid receptor agonists. Here, we describe the discovery and characterization of μ-opioid receptor PAMs and silent allosteric modulators, identified from high-throughput screening using a β-arrestin–recruitment assay.

Strategy for making safer opioids bolstered

“…Other approaches have involved molecules that bind to the µOR only in acidic environments 7 (which are often associated with damaged tissue), and compounds that target opioid receptors formed from more than one subtype 8 . A more-recent strategy has been to make allosteric modulators of the µOR -compounds that activate it by binding to a region on the receptor other than its active site 9 . Each of these approaches has enhanced our understanding of the µOR system, but has not led to the identification of a safe analgesic.…”

“…Estimates of ECS vary depending on the evidence used (such as records of Earth's energy budget 9 and analyses 4 of present climate conditions produced by models). The estimate 1 from the Intergovernmental Panel on Climate Change (IPCC) published in 2013 is based on several lines of evidence.…”

Disruption of the Na + ion binding site as a mechanism for positive allosteric modulation of the mu-opioid receptor

“…Second, the same degree of shift in the inhibitory effect of NaCl on DAMGO binding is seen with both 10 μM and 30 μM BMS-986122, suggesting saturation is reached as expected for allosterism, rather than the surmountable parallel shifts expected if the antagonism were competitive (40). Third, the Na + -H 2 O cluster binding pocket is conserved between MOPr and DOPr (24) and indeed across all Class A GPCRs (26), yet the PAM activity of BMS-986122 is selective for MOPr over DOPr (1).…”

“…Clinically used opioid agonists bind to the orthosteric site on MOPr and although they are efficacious at causing pain relief, have a number of unwanted side effects resulting from direct MOPr activation. We have recently discovered and presented a preliminary characterization of positive allosteric modulators of MOPr (mu-PAMs) and are currently pursuing the idea that mu-PAMs could be a viable way to manage pain (1,2). The ligand BMS-986122 (Fig.…”

“…Currently, it is not known if all opioid agonists are equally sensitive to the PAM effect of BMS-986122, nor the mechanism underlying the allosteric modulation. Our initial characterization showed that BMS-986122 causes a shift in the potency of the agonist DAMGO ([D-Ala 2 , N-MePhe 4 , Gly-ol]-enkephalin), but increases the maximal stimulation of G protein by morphine (1). Opioid ligands are extremely diverse, ranging from the 31-amino acid endogenous peptide β-endorphin to small alkaloids like morphine.…”