Biased Opioid Ligands.

Abdelfattah Faouzi,Susruta Majumdar,Balazs R Varga

doi:10.3390/molecules25184257

Abdelfattah Faouzi, Susruta Majumdar + Show 1 more

Open Access

https://doi.org/10.3390/molecules25184257

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Abstract

Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.

Highlights

G-protein coupled receptors (GPCRs) are a 7 transmembrane-spanning evolutionary conserved superfamily that has been well described in the literature and the subject of extensive studies for the last couple of decades [1,2]
At MOR, the response is mixed with attenuation of respiratory depression not correlating with βarrrestin-2 recruitment
The low respiratory depression of mitragynine(s) discussed in this manuscript may be a result of other targets, like DOR antagonism

Summary

Introduction

G-protein coupled receptors (GPCRs) are a 7 transmembrane-spanning evolutionary conserved superfamily that has been well described in the literature and the subject of extensive studies for the last couple of decades [1,2]. We will focus on the significance and potential future avenues for in as a credible strategy in order to mitigate analgesia from the classical opioids side effects It started the development biased ligands andantheir analogsantinociceptive targeting the opioid. KO mice in [18] These results were significant the opioid field created a whole new approach in the development of side effects was the focus of follow-up studies, which demonstrated reduced design of G protein-biased agonists, thought to be “better opioids” with an improved safety profile gastrointestinal, respiratory effects, and tolerance of morphine in β-arrestin. A non-exhaustive list of MOR biased ligands with potency and

Structures

KOR Biased Agonism

Biased Agonism on DOR

Biased Agonism on NOP Receptor

Future Directions and Conclusions

Methods