Utilizing Nature as a Source of New Probes for Opioid Pharmacology

Lovell, Kimberly M.; Simpson, Denise S.; Cunningham, Christopher W.; Prisinzano, Thomas E.

doi:10.4155/fmc.09.22

Cited by 4 publications

(6 citation statements)

References 134 publications

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“…Despite the large amounts of articles reporting on the pharmacological activities of flavonoids, relatively few studies on the opioid receptors’ binding affinity of these compounds have been reported. − In some works it has been demonstrated that the antinociceptive effect exerted by flavonoids in mouse thermal models of nociception was related to the activation of the opioid receptors. ,− Although some hydroxyflavones have been identified as opioid antagonists, none have been shown to inhibit morphine-induced antinociception in an animal model of acute pain. As far as we know, we reported for the first time that a flavone administered intraperitoneally in mice significantly reduced morphine-induced antinociception in a dose-dependent manner in the tail-flick test and that, in all probability, its action is mediated, at least in part, by opioid receptors.…”

Section: Resultsmentioning

confidence: 99%

Methoxyflavones fromStachys glutinosawith Binding Affinity to Opioid Receptors: In Silico, in Vitro, and in Vivo Studies

et al. 2015

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Fractionation of the bioactive dichloromethane extract from the aerial parts of Stachys glutinosa led to the isolation of four flavones, xanthomicrol (1), sideritoflavone (2), 8-methoxycirsilineol (3), and eupatilin (4), along with two neo-clerodane diterpenes, roseostachenone (8) and a new compound, 3α,4α-epoxyroseostachenol (7). In order to study structure-activity relationships, two methoxyflavones [5-demethyltangeretin (5) and tangeretin (6)] were synthesized by the methoxylation of xanthomicrol. The isolated compounds (1-4, 7, and 8) as well as the xanthomicrol semisynthetic derivatives (5 and 6) were evaluated for their binding affinity to the μ and δ opioid receptors. Xanthomicrol was the most potent binder to both μ and δ receptors, with a Ki value of 0.83 and 3.6 μM, respectively. Xanthomicrol administered intraperitoneally in mice at a dose of 80 mg/kg significantly reduced morphine-induced antinociception in the tail flick test. Our results suggested that xanthomicrol is a μ opioid receptor antagonist. Docking experiments were carried out to acquire a deeper understanding about important structural aspects of binding of xanthomicrol. In summary, these data suggest that xanthomicrol is a valuable structure for further development into a potential μ opioid receptor antagonist.

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Section: Resultsmentioning

confidence: 99%

Methoxyflavones fromStachys glutinosawith Binding Affinity to Opioid Receptors: In Silico, in Vitro, and in Vivo Studies

et al. 2015

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“…Bioassays with a series of other natural flavonoids including catechin ( 5 ) and hesperetin ( 6 ) have been conducted and demonstrate that this scaffold may have considerable potential for development of opioid receptor ligands . Other structural subtypes with opioid-binding activity are becoming more common, − including stilbenoids more reminiscent of the pawhuskins such as resveratrol ( 7 ) , and, more recently, chlorophorin ( 8 ) …”

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confidence: 99%

Stilbenes as κ-Selective, Non-nitrogenous Opioid Receptor Antagonists

et al. 2014

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The natural stilbene pawhuskin A has been shown to function as an opioid receptor antagonist, with preferential binding to the κ receptor. This finding encouraged assembly of a set of analogues to probe the importance of key structural features. Assays on these compounds determined that one (compound 29) shows potent opioid receptor binding activity and significantly improved selectivity for the κ receptor. These studies begin to illuminate the structural features of these non-nitrogenous opioid receptor antagonists that are required for activity.

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“…A minor pathway uses the same three-enzyme process. First, codeine-O-demethylase converts thebaine to the 3-phenol, oripavine (30), which is 6-O-demethylated and epimerized as described above (thebaine 6-O-demethylase) to afford morphinone (31). Ketone reduction (codeinone reductase) converts morphinone to morphine.…”

Section: ■ Street Namesmentioning

confidence: 99%

“…In a broader sense, the isolation of morphine from P. somniferum revolutionized the field of natural product-based drug discovery. , Plants and herbs, used for centuries by diverse cultures to treat disease, presented problems for Western medical practitioners. For one, Western medicinewhich relies on empiric, evidence-based treatmentssuffered from a lack of standardized biologic material with which to perform controlled clinical trials.…”

Section: Introductionmentioning

confidence: 99%

DARK Classics in Chemical Neuroscience: Morphine

Devereaux

Mercer

Cunningham

2018

ACS Chem. Neurosci.

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As the major psychoactive agent in opium and direct precursor for heroin, morphine is a historically critical molecule in chemical neuroscience. A structurally complex phenanthrene alkaloid produced by Papaver somniferum, morphine has fascinated chemists seeking to disentangle pharmacologically beneficial analgesic effects from addiction, tolerance, and dependence liabilities. In this review, we will detail the history of morphine, from the first extraction and isolation by Sertürner in 1804 to the illicit use of morphine and proliferation of opioid use and abuse disorders currently ravaging the United States. Morphine is a molecule of great cultural relevance, as the agent that single-handedly transformed our understanding of pharmacognosy, receptor dynamics, and substance abuse and dependence disorders.

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Utilizing Nature as a Source of New Probes for Opioid Pharmacology

Abstract: The strong history of natural products as opioid receptor ligands suggests that nature is one of the most promising for the identification of novel opioids. This review highlights the vast potential of investigating natural products as novel probes of opioid receptors.

Cited by 4 publications

References 134 publications

Methoxyflavones fromStachys glutinosawith Binding Affinity to Opioid Receptors: In Silico, in Vitro, and in Vivo Studies

Methoxyflavones fromStachys glutinosawith Binding Affinity to Opioid Receptors: In Silico, in Vitro, and in Vivo Studies

Stilbenes as κ-Selective, Non-nitrogenous Opioid Receptor Antagonists

DARK Classics in Chemical Neuroscience: Morphine

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