DARK Classics in Chemical Neuroscience: Morphine

Devereaux, Andrea L.; Mercer, Susan L.; Cunningham, Christopher W.

doi:10.1021/acschemneuro.8b00150

Cited by 69 publications

(51 citation statements)

References 163 publications

(267 reference statements)

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“…In fact, removal of rings B, C, and E from morphine led to a development of phenylpiperidine series that maintained the analgesic activity, and introduction of nitrogen led to the formation of 4-anilidopiperidine class of fentanyl and its analogues [27]. Listed as a "category A" analytical technique by Scientific Working Group for the Analysis of Seized Drugs (SWG-DRUG) [28], Raman spectroscopy is considered with the highest potential discriminating power for the analysis of controlled substances.…”

Section: Sers and Raman Spectrometric Characteristic Of Fentanyls Andmentioning

confidence: 99%

Elucidating fentanyls differentiation from morphines in chemical and biological samples with surface‐enhanced Raman spectroscopy

Wang

et al. 2019

Electrophoresis

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Fentanyl and morphine are opioid drugs as well as new psychoactive substances. Even originally introduced as efficient anesthetic drugs to relieve moderate‐to‐severe pain in clinic, the overdose of new synthetic opioids is currently a serious public health problem in numerous countries worldwide. The entire category of fentanyls has been included in the regulatory list in several countries. There is a great and urgent demand to rapidly recognize fentanyls and morphines in various samples. Here, we report an on‐site surface‐enhanced Raman spectroscopic method to classify fentanyls from morphines by the Raman spectroscopic signature of the molecular scaffold structure, with an assistance of principle component analysis algorithm. Moreover, by simple but fine‐tuning approach of inorganic salt‐induced aggregation of gold nanoparticles substrate, we achieved a selective detection of 10 ng/mL fentanyl from 2000‐fold of heroin, the most common coexisting substance in chemical samples. Good differentiation of 50 ng/mL fentanyl from 10 000‐fold morphine as a main metabolite of heroin in urine samples was also possible after a feasible pretreatment by StageTip procedures. Depending on different structures, the detection sensitivity of five fentanyls ranged from 50 to 2000 ng/mL.

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Section: Sers and Raman Spectrometric Characteristic Of Fentanyls Andmentioning

confidence: 99%

Elucidating fentanyls differentiation from morphines in chemical and biological samples with surface‐enhanced Raman spectroscopy

Wang

et al. 2019

Electrophoresis

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“…Corydine (1) and corydaline (2) are two naturally occurring alkaloids in different Corydalis and Berberis species 45,[55][56][57][58][59][60] that are used as medicinal plants to treat pain (spastic pain, abdominal pain, or pain due to injury) and other human ailments [61][62][63][64] . Plant extracts and isolated alkaloids, mostly corydaline (2), were reported to produce antinociceptive effects in rodents 59,[65][66][67][68] , although no mechanism of action was associated to the observed pain inhibitory effects so far.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of plant-derived alkaloids, corydine and corydaline, as novel mu opioid receptor agonists

Kaserer

Steinacher

Kainhofer

et al. 2020

Sci Rep

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Pain remains a key therapeutic area with intensive efforts directed toward finding effective and safer analgesics in light of the ongoing opioid crisis. Amongst the neurotransmitter systems involved in pain perception and modulation, the mu-opioid receptor (MOR), a G protein-coupled receptor, represents one of the most important targets for achieving effective pain relief. Most clinically used opioid analgesics are agonists to the MOR, but they can also cause severe side effects. Medicinal plants represent important sources of new drug candidates, with morphine and its semisynthetic analogues as well-known examples as analgesic drugs. In this study, combining in silico (pharmacophorebased virtual screening and docking) and pharmacological (in vitro binding and functional assays, and behavioral tests) approaches, we report on the discovery of two naturally occurring plant alkaloids, corydine and corydaline, as new MOR agonists that produce antinociceptive effects in mice after subcutaneous administration via a MOR-dependent mechanism. Furthermore, corydine and corydaline were identified as G protein-biased agonists to the MOR without inducing β-arrestin2 recruitment upon receptor activation. Thus, these new scaffolds represent valuable starting points for future chemical optimization towards the development of novel opioid analgesics, which may exhibit improved therapeutic profiles. Naturally occurring opioid alkaloids, such as morphine (Fig. 1), have been used for centuries for severe and chronic pain relief 1. Over several decades, new opioids with diverse scaffolds were synthesized, pharmacologically evaluated and clinically used as the most effective class of analgesic drugs 2-5. However, all currently available opioid analgesics share a similar spectrum of undesirable side effects, including respiratory depression, constipation, sedation, nausea and analgesic tolerance 5,6. Additionally, the potential for addiction and abuse of opioids has seriously hindered their clinical application, with a huge rise in opioid misuse and overdose deaths resulting in an ongoing and rapidly emerging opioid epidemic worldwide 7,8. Currently, intensive research focuses on finding new, innovative medications and technologies to treat opioid addiction, together with the discovery of safe, effective, non-addictive drugs to manage chronic pain 9-12. Opioids produce their pharmacological effects through the activation of opioid receptors, which include three main types, mu (MOR), delta (DOR) and kappa (KOR) 13,14 , of which the MOR type is the primary target of most clinically used opioid analgesics 3,5. Opioid receptors share high homology and belong to the superfamily of seven transmembrane-spanning G protein-coupled receptors (GPCRs). Because of its therapeutic relevance, the MOR is among the few GPCRs determined in different activation states, with the first X-ray crystal structure of the receptor protein bound to β-funaltrexamine (Fig. 1), an irreversible antagonist (PDB entry 4DKL) 15 , and the 3D-structure in the active confo...

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“…The general structure‐activity relationships (SARs) of morphine and 4,5‐epoxymorphinans have recently been reviewed . The pharmacophore consists of a weakly basic tertiary amino function protonated at physiologic pH, separated by a short carbon linker from an aromatic ring.…”

Section: Acid‐base Propertiesmentioning

confidence: 99%

“…[14,15] The general structure-activity relationships (SARs) of morphine and 4,5-epoxymorphinans have recently been reviewed. [16,17] The pharmacophore consists of a weakly basic tertiary amino function protonated at physiologic pH, separated by a short carbon linker from an aromatic ring. The potency is enhanced when the C3 phenol group is intact, as this imitates the N-terminal tyrosine of endogenous opioid peptides (enkephalins, endorphins).…”

Section: Acid-base Propertiesmentioning

confidence: 99%

Advances in the Physicochemical Profiling of Opioid Compounds of Therapeutic Interest

2019

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This review focuses on recent developments in the physicochemical profiling of morphine and other opioids. The acid‐base properties and lipophilicity of these compounds is discussed at the microscopic, species‐specific level. Examples are provided where this type of information can reveal the mechanism of pharmacokinetic processes at the submolecular level. The role of lipophilicity in quantitative structure–activity relationship (QSAR) studies of opioids is reviewed. The physicochemical properties and pharmacology of the main metabolites of morphine are also discussed. Recent studies indicate that the active metabolite morphine‐6‐glucuronide (M6G) can contribute to the analgesic activity of systemically administered morphine. The unexpectedly high lipophilicity of M6G partly accounts for its analgesic activity. When administered parenterally, another suspected minor metabolite, morphine‐6‐sulfate (M6S) has superior antinociceptive effects to those of morphine. However, because sulfate esters of morphine derivatives cannot cross the blood‐brain barrier these esters may be good candidates to develop peripheral analgesic drugs.

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DARK Classics in Chemical Neuroscience: Morphine

Cited by 69 publications

References 163 publications

Elucidating fentanyls differentiation from morphines in chemical and biological samples with surface‐enhanced Raman spectroscopy

Elucidating fentanyls differentiation from morphines in chemical and biological samples with surface‐enhanced Raman spectroscopy

Identification and characterization of plant-derived alkaloids, corydine and corydaline, as novel mu opioid receptor agonists

Advances in the Physicochemical Profiling of Opioid Compounds of Therapeutic Interest

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