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Effects of two structurally diverse positive allosteric modulators on signaling bias at the μ-opioid receptor
Mengchu Li1, Kelsey E Kochan1, M Alexander Stanczyk1
1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan.
Abstract:
The μ-opioid receptor (MOR) is responsible for the analgesic actions of opioid drugs as well as their unwanted actions, including respiratory depression and addiction liability. Following agonist occupancy, MOR can signal via G-protein and/or β-arrestin. However, MOR agonists may show an imbalance between activating these 2 pathways. Evidence from studies of G-protein-coupled receptors suggests that allosteric modulators can influence agonist signaling profiles. However, no studies have examined this phenomenon at MOR. In this study, we compare the ability of various orthosteric MOR agonists to activate G-protein or recruit β-arrestin in the absence or presence of 2 structurally distinct MOR positive allosteric modulators, BMS-986187 (a xanthenedione) or BMS-986122 (a thiazolidine). We determined the potency and efficacy of 6 orthosteric agonists (DAMGO, fentanyl, methadone, morphine, Met-enkephalin, and SR17018) with and without BMS-986187 or BMS-986122, and determined bias factors for the agonists themselves and in the presence of a modulator. The 2 allosteric modulators enhanced the potency of agonists to different degrees showing probe dependence and differentially shifted the ability of agonists to activate G-protein as compared to recruitment of β-arrestin, indicating an effect on ligand bias. In both measures, in the presence of either modulator, the higher efficacy agonists showed a shift in potency. In contrast, lower efficacy compounds showed an increase in maximal effect with a smaller shift in potency. Overall, the studies provide evidence that positive allosteric modulators influence the degree and direction by which orthosteric agonists signal downstream of MOR. SIGNIFICANCE STATEMENT: Biased agonism and positive allosteric modulation at the μ-opioid receptor have been suggested as approaches to improve the therapeutic index of opioid agonists. This work shows how allosteric modulation alters the bias signaling profile of μ-opioid agonists.
Insights
Positive allosteric modulators alter how μ-opioid receptor (MOR) agonists activate G-protein versus β-arrestin pathways. This finding is crucial for developing safer opioid analgesics with reduced side effects like addiction.
Area of Science:
- Pharmacology
- Neuroscience
- Molecular Biology
Background:
- The μ-opioid receptor (MOR) mediates both therapeutic effects (analgesia) and adverse effects (respiratory depression, addiction) of opioids.
- MOR activation can trigger distinct signaling pathways, primarily G-protein and β-arrestin, and an imbalance in these pathways is linked to side effects.
- Allosteric modulators are known to influence G-protein-coupled receptor signaling, but their effect on MOR signaling bias has not been previously investigated.
Purpose of the Study:
- To investigate the impact of two distinct MOR positive allosteric modulators (BMS-986187 and BMS-986122) on the signaling bias of various orthosteric MOR agonists.
- To determine how these allosteric modulators affect the potency and efficacy of agonists in activating G-protein versus β-arrestin pathways.
Main Methods:
- Assessed the potency and efficacy of six orthosteric MOR agonists (DAMGO, fentanyl, methadone, morphine, Met-enkephalin, SR17018) in activating G-protein and recruiting β-arrestin.
- Performed these assessments in the absence and presence of the two MOR positive allosteric modulators (BMS-986187 and BMS-986122).
- Calculated bias factors to quantify the signaling bias of agonists alone and in combination with modulators.
Main Results:
- Both allosteric modulators enhanced agonist potency to varying degrees, demonstrating probe dependence.
- The modulators differentially shifted the G-protein activation versus β-arrestin recruitment balance, indicating an alteration in ligand bias.
- Higher efficacy agonists showed a shift in potency, while lower efficacy agonists exhibited increased maximal effects with smaller potency shifts in the presence of modulators.
Conclusions:
- Positive allosteric modulators significantly influence the signaling profile of orthosteric MOR agonists, affecting both the degree and direction of G-protein and β-arrestin pathway activation.
- These findings support the potential of biased agonism and positive allosteric modulation as strategies to improve the therapeutic index of MOR agonists.
- Understanding how allosteric modulators fine-tune MOR signaling bias is critical for developing safer and more effective opioid-based therapeutics.
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