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Science (New York, N.Y.) Oct 2018Morphinan-based painkillers are derived from opium poppy ( L.). We report a draft of the opium poppy genome, with 2.72 gigabases assembled into 11 chromosomes with...
Morphinan-based painkillers are derived from opium poppy ( L.). We report a draft of the opium poppy genome, with 2.72 gigabases assembled into 11 chromosomes with contig N50 and scaffold N50 of 1.77 and 204 megabases, respectively. Synteny analysis suggests a whole-genome duplication at ~7.8 million years ago and ancient segmental or whole-genome duplication(s) that occurred before the Papaveraceae-Ranunculaceae divergence 110 million years ago. Syntenic blocks representative of phthalideisoquinoline and morphinan components of a benzylisoquinoline alkaloid cluster of 15 genes provide insight into how this cluster evolved. Paralog analysis identified P450 and oxidoreductase genes that combined to form the gene fusion essential for morphinan biosynthesis in opium poppy. Thus, gene duplication, rearrangement, and fusion events have led to evolution of specialized metabolic products in opium poppy.
Topics: Benzylisoquinolines; Evolution, Molecular; Gene Duplication; Gene Fusion; Gene Order; Genome, Plant; Morphinans; Multigene Family; NADPH-Ferrihemoprotein Reductase; Papaver; Plant Proteins; Synteny
PubMed: 30166436
DOI: 10.1126/science.aat4096 -
Psychopharmacology Aug 2020Prolinol aryl ethers and their rigidified analogues pyrrolidinyl benzodioxanes have a high affinity for mammalian α4β2 nicotinic acetylcholine receptors (nAChRs)....
Behavioural and pharmacological profiles of zebrafish administrated pyrrolidinyl benzodioxanes and prolinol aryl ethers with high affinity for heteromeric nicotinic acetylcholine receptors.
RATIONALE
Prolinol aryl ethers and their rigidified analogues pyrrolidinyl benzodioxanes have a high affinity for mammalian α4β2 nicotinic acetylcholine receptors (nAChRs). Electrophysiological studies have shown that the former are full agonists and the latter partial agonists or antagonists of human α4β2 receptors, but their in vivo effects are unknown.
OBJECTIVES AND METHODS
As α4β2 nAChRs play an important role in the cognition and the rewarding effects of nicotine, we tested the effects of two full agonists and one antagonist on spatial learning, memory and attention in zebrafish using a T-maze task and virtual object recognition test (VORT). The effect of a partial agonist in reducing nicotine-induced conditioned place preference (CPP) was also investigated.
RESULTS
In comparison with the vehicle alone, the full agonists MCL-11 and MCL-28 induced a significant cognitive enhancement as measured by the reduced running time in the T-maze and increased attention as measured by the increased discrimination index in the VORT. MCL-11 was 882 times more potent than nicotine. The two compounds were characterised by an inverted U-shaped dose-response curve, and their effects were blocked by the co-administration of the antagonist MCL-117, which alone had no effect. The partial agonist MCL-54 induced CPP and had an inverted U-shaped dose-response curve similar to that of nicotine but blocked the reinforcing effect of co-administered nicotine. Binding studies showed that all of the compounds have a higher affinity for heteromeric [H]-epibatidine receptors than [I]-αBungarotoxin receptors. MCL-11 was the most selective of heteromeric receptors.
CONCLUSIONS
These behavioural studies indicate that full agonist prolinol aryl ethers are very active in increasing spatial learning, memory and attention in zebrafish. The benzodioxane partial agonist MCL-54 reduced nicotine-induced CPP, and the benzodioxane antagonist MCL-117 blocked all agonist-induced activities.
Topics: Animals; Dose-Response Relationship, Drug; Ethers; Female; Male; Maze Learning; Morphinans; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Pyrrolidines; Pyrrolidinones; Receptors, Nicotinic; Zebrafish
PubMed: 32382782
DOI: 10.1007/s00213-020-05536-6 -
Molecules (Basel, Switzerland) Dec 2022Sinomenine is the main component of the vine . It was first isolated in the early 1920s and has since attracted special interest as a potential anti-rheumatoid arthritis... (Review)
Review
Sinomenine is the main component of the vine . It was first isolated in the early 1920s and has since attracted special interest as a potential anti-rheumatoid arthritis (RA) agent, owing to its successful application in traditional Chinese medicine for the treatment of neuralgia and rheumatoid diseases. In the past few decades, significant advances have broadened our understanding of the molecular mechanisms through which sinomenine treats RA, as well as the structural modifications necessary for improved pharmacological activity. In this review, we summarize up-to-date reports on the pharmacological properties of sinomenine in RA treatment, document their underlying mechanisms, and provide an overview of promising sinomenine derivatives as potential RA drug therapies.
Topics: Humans; Arthritis, Rheumatoid; Morphinans; Medicine, Chinese Traditional; Neuralgia
PubMed: 36557779
DOI: 10.3390/molecules27248645 -
Science (New York, N.Y.) Sep 2015Opioids are the primary drugs used in Western medicine for pain management and palliative care. Farming of opium poppies remains the sole source of these essential...
Opioids are the primary drugs used in Western medicine for pain management and palliative care. Farming of opium poppies remains the sole source of these essential medicines, despite diverse market demands and uncertainty in crop yields due to weather, climate change, and pests. We engineered yeast to produce the selected opioid compounds thebaine and hydrocodone starting from sugar. All work was conducted in a laboratory that is permitted and secured for work with controlled substances. We combined enzyme discovery, enzyme engineering, and pathway and strain optimization to realize full opiate biosynthesis in yeast. The resulting opioid biosynthesis strains required the expression of 21 (thebaine) and 23 (hydrocodone) enzyme activities from plants, mammals, bacteria, and yeast itself. This is a proof of principle, and major hurdles remain before optimization and scale-up could be achieved. Open discussions of options for governing this technology are also needed in order to responsibly realize alternative supplies for these medically relevant compounds.
Topics: Animals; Benzylisoquinolines; Biosynthetic Pathways; Carbohydrate Metabolism; Codeine; Genetic Engineering; Hydrocodone; Morphinans; Papaver; Saccharomyces cerevisiae; Thebaine
PubMed: 26272907
DOI: 10.1126/science.aac9373 -
Chemistry (Weinheim An Der Bergstrasse,... Mar 2020N-Demethylation of oxycodone is one of the key steps in the synthesis of important opioid antagonists like naloxone or analgesics like nalbuphine. The reaction is...
N-Demethylation of oxycodone is one of the key steps in the synthesis of important opioid antagonists like naloxone or analgesics like nalbuphine. The reaction is typically carried out using stoichiometric amounts of toxic and corrosive reagents. Herein, we present a green and scalable organophotocatalytic procedure that accomplishes the N-demethylation step using molecular oxygen as the terminal oxidant and an organic dye (rose bengal) as an effective photocatalyst. Optimization of the reaction conditions under continuous flow conditions using visible-light irradiation led to an efficient, reliable, and scalable process, producing noroxycodone hydrochloride in high isolated yield and purity after a simple workup.
Topics: Analgesics; Demethylation; Humans; Morphinans; Oxycodone
PubMed: 31898822
DOI: 10.1002/chem.201905505 -
Organic Letters Sep 2020The most challenging step in the preparation of many opioid antagonists is the selective -demethylation of a 14-hydroxymorphinan precursor. This process is carried out...
The most challenging step in the preparation of many opioid antagonists is the selective -demethylation of a 14-hydroxymorphinan precursor. This process is carried out on a large scale using stoichiometric amounts of hazardous chemicals like cyanogen bromide or chloroformates. We have developed a mild reagent- and catalyst-free procedure for the -demethylation step based on the anodic oxidation of the tertiary amine. The ensuing intermediates can be readily hydrolyzed to the target nor-opioids in very good yields.
Topics: Analgesics, Opioid; Catalysis; Demethylation; Hydrolysis; Molecular Structure; Morphinans; Narcotic Antagonists; Oxidation-Reduction
PubMed: 32790319
DOI: 10.1021/acs.orglett.0c02424 -
Nature Aug 2015µ-Opioid receptors (µORs) are G-protein-coupled receptors that are activated by a structurally diverse spectrum of natural and synthetic agonists including endogenous...
µ-Opioid receptors (µORs) are G-protein-coupled receptors that are activated by a structurally diverse spectrum of natural and synthetic agonists including endogenous endorphin peptides, morphine and methadone. The recent structures of the μOR in inactive and agonist-induced active states (Huang et al., ref. 2) provide snapshots of the receptor at the beginning and end of a signalling event, but little is known about the dynamic sequence of events that span these two states. Here we use solution-state NMR to examine the process of μOR activation using a purified receptor (mouse sequence) preparation in an amphiphile membrane-like environment. We obtain spectra of the μOR in the absence of ligand, and in the presence of the high-affinity agonist BU72 alone, or with BU72 and a G protein mimetic nanobody. Our results show that conformational changes in transmembrane segments 5 and 6 (TM5 and TM6), which are required for the full engagement of a G protein, are almost completely dependent on the presence of both the agonist and the G protein mimetic nanobody, revealing a weak allosteric coupling between the agonist-binding pocket and the G-protein-coupling interface (TM5 and TM6), similar to that observed for the β2-adrenergic receptor. Unexpectedly, in the presence of agonist alone, we find larger spectral changes involving intracellular loop 1 and helix 8 compared to changes in TM5 and TM6. These results suggest that one or both of these domains may play a role in the initial interaction with the G protein, and that TM5 and TM6 are only engaged later in the process of complex formation. The initial interactions between the G protein and intracellular loop 1 and/or helix 8 may be involved in G-protein coupling specificity, as has been suggested for other family A G-protein-coupled receptors.
Topics: Allosteric Regulation; Animals; Binding Sites; Heterotrimeric GTP-Binding Proteins; Lysine; Mice; Models, Molecular; Morphinans; Nuclear Magnetic Resonance, Biomolecular; Protein Binding; Protein Conformation; Pyrroles; Receptors, Adrenergic, beta-2; Receptors, Opioid, mu; Single-Chain Antibodies; Structure-Activity Relationship; Substrate Specificity
PubMed: 26245377
DOI: 10.1038/nature14680 -
Medicine Dec 2023In traditional Chinese medicine, Sinomenii Caulis contains Sinomenine (SIN), one of the major active ingredients. According to some studies, SIN can reduce proteinuria... (Meta-Analysis)
Meta-Analysis
BACKGROUND
In traditional Chinese medicine, Sinomenii Caulis contains Sinomenine (SIN), one of the major active ingredients. According to some studies, SIN can reduce proteinuria and provides clinical effectiveness rates in diabetic kidney disease (DKD) patients, however, the evidence is not strong and mechanisms of action are unclear. The efficacy and safety of SIN in treating DKD were evaluated by meta-analysis, and the potential mechanism of SIN therapy for DKD was initially explored by network pharmacology.
METHODS
PubMed, Cochrane Library, Embase, Web of Science, CNKI, Wanfang, VIP, and SinoMed databases were comprehensively searched until March 28, 2022. Randomized controlled trials on DKD treated with SIN were selected. The main results were clinical effective rate and the secondary results were the decrease in 24-hour urine total protein (24-hour UTP), serum creatinine, adverse reactions, etc. Drug combinations and disease stages were analyzed in subgroups. Sensitivity analysis was performed for 24-hour UTP. The potential target genes and pathways of SIN in treating DKD were studied using protein-protein interactions, gene ontology, and the Kyoto Genome Encyclopedia and Genomes enrichment analysis.
RESULTS
The meta-analysis included 7 randomized controlled trials. SIN treatment had a higher clinical effectiveness rate than conventional treatment (relative risk = 1.53, 95% confidence interval [1.30; 1.80], Z = 5.14, P < .0001); the decrease in 24-hour UTP, treatment group was higher than control group (standardized mean difference = -1.12, 95% confidence interval [-1.71; -0.52], Z = -3.69, P = .0002); In the experimental group, adverse reactions were more common than in the control group. SIN mainly affected 5 target genes, NFκB-1, TNF, interleukin 6, interleukin 1β and signal transducer and activator of transcription 3, and IL-17, AGE-RAGE signaling pathways, lipids, and atherosclerosis were all controlled to achieve therapeutic effects.
CONCLUSION
SIN is an effective and safe drug for treating DKD, enhancing clinical efficacy, and reducing proteinuria. The main potential mechanism is anti-inflammatory.
Topics: Humans; Diabetes Mellitus; Diabetic Nephropathies; Morphinans; Proteinuria
PubMed: 38206710
DOI: 10.1097/MD.0000000000036779 -
The American Journal of Case Reports Sep 2017BACKGROUND Sinomenine hydrochloride is an alkaloid that is extracted from the Chinese herbal plant Sinomenium acutum, and is used as a herbal medicine in the treatment...
BACKGROUND Sinomenine hydrochloride is an alkaloid that is extracted from the Chinese herbal plant Sinomenium acutum, and is used as a herbal medicine in the treatment or rheumatic disease. This report is the first to describe a case of sinomenine hydrochloride-induced agranulocytosis. CASE REPORT A 44-year-old woman with systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) was treated with sinomenine hydrochloride and developed agranulocytosis with a neutrophil count of 0.01×10^9/L. She subsequently developed an opportunistic bacterial infection. Bone marrow aspiration showed a severe reduction in the proportion of mature granulocytes. The patient discontinued sinomenine hydrochloride therapy and was treated with granulocyte colony-stimulating factor (G-CSF) and antibiotics. The patient showed a return to normal granulocyte levels within ten days of discontinuing treatment with sinomenine hydrochloride. CONCLUSIONS The findings of this case report show that monitoring of bone marrow function and granulocyte levels should be performed during treatment with sinomenine hydrochloride.
Topics: Adult; Agranulocytosis; Antirheumatic Agents; Drugs, Chinese Herbal; Female; Humans; Morphinans
PubMed: 28874654
DOI: 10.12659/ajcr.904519 -
Hypertension (Dallas, Tex. : 1979) Feb 2022Nalfurafine is a G-protein-biased KOR (kappa opioid receptor) agonist that produces analgesia and lacks central nervous system adverse effects. Here, we examined the...
Nalfurafine is a G-protein-biased KOR (kappa opioid receptor) agonist that produces analgesia and lacks central nervous system adverse effects. Here, we examined the cardiovascular and renal responses to intravenous and oral nalfurafine alone and in combination with furosemide, hydrochlorothiazide, or amiloride. We hypothesized that nalfurafine, given its distinct mechanism of vasopressin inhibition, would increase urine output to these diuretics and limit electrolyte loss. Following catheterization, conscious Sprague-Dawley rats received an isotonic saline infusion and were then administered an intravenous bolus of nalfurafine, a diuretic, or a combination. Mean arterial pressure, heart rate, and urine output were recorded for 90 minutes. In another study, rats were placed in metabolic cages and administered drug in an oral volume load. Hourly urine samples were then collected for 5 hours. Intravenous and oral nalfurafine produced a marked diuresis, antinatriuresis, antikaliuresis, and a decrease in mean arterial pressure. Compared with diuretic treatment alone, intravenous coadministration with nalfurafine significantly increased urine output to furosemide and hydrochlorothiazide and decreased sodium and potassium excretion. Notably, mean arterial pressure was reduced with nalfurafine/diuretic combination therapy compared to diuretics alone. Similarly, oral coadministration of nalfurafine significantly increased urine output to hydrochlorothiazide and decreased sodium and potassium excretion, whereas combination with furosemide only limited the amount of sodium excreted. Further, both intravenous and oral coadministration of nalfurafine enhanced the diuresis to amiloride and decreased sodium excretion. Together, these findings demonstrate that nalfurafine enhances the diuresis to standard-of-care diuretics without causing an excessive loss of electrolytes, offering a new approach to treat several cardiovascular conditions.
Topics: Analgesics, Opioid; Animals; Diuresis; Diuretics; Furosemide; Hydrochlorothiazide; Kidney; Male; Morphinans; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Spiro Compounds
PubMed: 34852633
DOI: 10.1161/HYPERTENSIONAHA.121.18503