Strategy for making safer opioids bolstered

Majumdar, Susruta; Devi, Lakshmi A.

doi:10.1038/d41586-018-00045-1

Cited by 25 publications

(26 citation statements)

References 19 publications

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“…For example, other MOR agonists that activate G protein signaling without recruiting the beta-arrestin pathway exhibit attenuated respiratory depression and reduced inhibition of gastrointestinal (GI) transit compared to classical opioids. 26−30 In fact, an early study on the pharmacology of mitragynine demonstrated its superiority compared to the classical opioid codeine in this regard, providing preliminary support for this hypothesis. 24 Similarly, mitragynine pseudoindoxyl, a chemical rearrangement product of 7-OH, has been found to be both G-protein biased and exhibit an improved therapeutic window in mice.…”

Section: Introductionmentioning

confidence: 95%

7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects

et al. 2019

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Mitragyna speciosa , more commonly known as kratom, is a plant native to Southeast Asia, the leaves of which have been used traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently, growing use of the plant in the United States and concerns that kratom represents an uncontrolled drug with potential abuse liability, have highlighted the need for more careful study of its pharmacological activity. The major active alkaloid found in kratom, mitragynine, has been reported to have opioid agonist and analgesic activity in vitro and in animal models, consistent with the purported effects of kratom leaf in humans. However, preliminary research has provided some evidence that mitragynine and related compounds may act as atypical opioid agonists, inducing therapeutic effects such as analgesia, while limiting the negative side effects typical of classical opioids. Here we report evidence that an active metabolite plays an important role in mediating the analgesic effects of mitragynine. We find that mitragynine is converted in vitro in both mouse and human liver preparations to the much more potent mu-opioid receptor agonist 7-hydroxymitragynine and that this conversion is mediated by cytochrome P450 3A isoforms. Further, we show that 7-hydroxymitragynine is formed from mitragynine in mice and that brain concentrations of this metabolite are sufficient to explain most or all of the opioid-receptor-mediated analgesic activity of mitragynine. At the same time, mitragynine is found in the brains of mice at very high concentrations relative to its opioid receptor binding affinity, suggesting that it does not directly activate opioid receptors. The results presented here provide a metabolism-dependent mechanism for the analgesic effects of mitragynine and clarify the importance of route of administration for determining the activity of this compound. Further, they raise important questions about the interpretation of existing data on mitragynine and highlight critical areas for further research in animals and humans.

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Section: Introductionmentioning

confidence: 95%

7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects

et al. 2019

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“…Studies have indicated that MOR signaling through G i (the inhibitory G protein for adenylyl cyclase) has a key role in the desired analgesic properties of morphine, whereas signaling through β-arrestin is associated with adverse side effects such as respiratory depression 162,163 . This knowledge has led to efforts to identify biased MOR ligands that show enhanced G i signaling and reduced β-arrestin signaling compared with morphine, including oliceridine (TRV130) 164 , PZM21 57 and SR17018 55,56 , which result in increased analgesia with reduced on-target adverse effects 52,53,57 . Further understanding of the mechanisms underlying biased MOR signaling are therefore of high interest for the development of much-needed novel analgesics.…”

Section: Nmr Studies Of Human Gpcrsmentioning

confidence: 99%

GPCR drug discovery: integrating solution NMR data with crystal and cryo-EM structures

Shimada

Ueda

Kofuku

et al. 2018

Nat Rev Drug Discov

206

174

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The 826 G protein-coupled receptors (GPCRs) in the human proteome regulate key physiological processes, and thus have long been attractive as drug targets. With crystal structure determinations of more than 50 different human GPCRs during the last decade, an initial platform for structure-based rational design has been established for drugs that target GPCRs, which is currently being augmented with cryo-EM structures of higher-order GPCR complexes. Nuclear magnetic resonance (NMR) spectroscopy in solution is one of the key approaches for expanding this platform with dynamic features, which can be accessed at physiological temperature and with minimal modification of the wild-type GPCR covalent structures. Here, we review strategies for the use of advanced biochemistry and NMR techniques with GPCRs, survey projects where crystal or cryo-EM structures have been complemented with NMR investigations, and discuss the impact of this integrative approach on GPCR biology and drug discovery. More than 30% of all drugs approved by the US Food and Drug Administration target G protein-coupled receptors (GPCRs)1–3, and these drugs are utilized in a wide range of therapeutic areas, including inflammation and diseases of the central nervous system as well as the cardiovascular, respiratory and gastrointestinal systems2,4. Currently more than 300 agents are in clinical trials, of which around 60 target novel GPCRs for which no drug has as yet been approved2. The novel GPCR targets also include orphan GPCRs, for which endogenous ligands have not yet been discovered2. Overall, the drugs approved so far target only 27% of the human non-olfactory GPCRs2, indicating that much excitement still lies ahead. Identifying new GPCR drugs will need additional detailed knowledge of GPCR biology, especially knowledge from structural biology, given the complex structure–function relationships involved in GPCR signaling. Along this line, recent reviews on GPCRs have covered studies with antibodies5 and nanobodies6, allosteric modulation7–10 biased signaling11–15, methods in GPCR structural biology16–19, GPCR crystal structures20–27 and drug development2,4,28,29, with some reviews addressing specific GPCR families30,31. Complementing the substantial number of GPCR crystal structures that have become available in the past decade, as well as the recent demonstrations of the potential for cryo-EM to provide information on higher-order GPCR complexes32–36, dynamic studies of GPCRs are important for providing new insights into GPCR biology that can assist drug discovery. In this respect, nuclear magnetic resonance (NMR) spectroscopy in solution is a key tool for analysing function-related conformational equilibria in GPCRs as they relate to allosteric coupling, variable efficacies and biased signaling of GPCR ligands, which are of particular interest for their potential as drugs. Furthermore, NMR spectroscopy is also a useful tool for fragment-based lead discovery with GPCR targets. In this article, we first overview the structural biology of GPCRs ba...

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“…Both compounds had similar G-protein potency and efficacy. Taking together comparative bias studies with biased/balanced agonist pairs, namely SR 17018 and SR11501 [ 51 ] and compounds 2 and 3 on this template, shows how small changes of chemical structure can lead to the engagement and disengagement of β-arrestin 2 while retaining G-protein potency. Additional studies are still ongoing, which the authors hope will guide the design of safer analgesics in the near future.…”

Section: Mor Biased Agonismmentioning

confidence: 99%

Biased Opioid Ligands

2020

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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.

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Strategy for making safer opioids bolstered

Cited by 25 publications

References 19 publications

7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects

7-Hydroxymitragynine Is an Active Metabolite of Mitragynine and a Key Mediator of Its Analgesic Effects

GPCR drug discovery: integrating solution NMR data with crystal and cryo-EM structures

Biased Opioid Ligands

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