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PloS One 2015Morphinan alkaloids are the most powerful narcotic analgesics currently used to treat moderate to severe and chronic pain. The feasibility of morphinan synthesis in...
Morphinan alkaloids are the most powerful narcotic analgesics currently used to treat moderate to severe and chronic pain. The feasibility of morphinan synthesis in recombinant Saccharomyces cerevisiae starting from the precursor (R,S)-norlaudanosoline was investigated. Chiral analysis of the reticuline produced by the expression of opium poppy methyltransferases showed strict enantioselectivity for (S)-reticuline starting from (R,S)-norlaudanosoline. In addition, the P. somniferum enzymes salutaridine synthase (PsSAS), salutaridine reductase (PsSAR) and salutaridinol acetyltransferase (PsSAT) were functionally co-expressed in S. cerevisiae and optimization of the pH conditions allowed for productive spontaneous rearrangement of salutaridinol-7-O-acetate and synthesis of thebaine from (R)-reticuline. Finally, we reconstituted a 7-gene pathway for the production of codeine and morphine from (R)-reticuline. Yeast cell feeding assays using (R)-reticuline, salutaridine or codeine as substrates showed that all enzymes were functionally co-expressed in yeast and that activity of salutaridine reductase and codeine-O-demethylase likely limit flux to morphine synthesis. The results of this study describe a significant advance for the synthesis of morphinans in S. cerevisiae and pave the way for their complete synthesis in recombinant microbes.
Topics: Chromatography, High Pressure Liquid; Fourier Analysis; Mass Spectrometry; Morphinans; Saccharomyces cerevisiae; Stereoisomerism
PubMed: 25905794
DOI: 10.1371/journal.pone.0124459 -
Journal of Oleo Science 2021Atherosclerosis (AS) is a cardiovascular disease that arise due to dysfunction of lipid deposition and metabolism. AS is causes the mortality and morbidity worldwide....
Atherosclerosis (AS) is a cardiovascular disease that arise due to dysfunction of lipid deposition and metabolism. AS is causes the mortality and morbidity worldwide. Sinomenine isolated from the Sinomenium acutum is used extensively against the various cardiac diseases in China. However, the anti-atherosclerosis effect of sinomenine still not explore. In this study, we explore the cardioprotective and anti-atherosclerosis effect of sinomenine against Vitamin D3 and High fat induced atherosclerosis in rats. Sprague Dawley (SD) rats were used in this study. The rats were received the vitamin D (60000) and High fat diet to induce the atherosclerosis and divided into groups and received the oral administration of sinomenine (2.5, 5 and 10 mg/kg) and simvastatin (5 mg/kg). Body weight, organ weight and biochemical parameters were estimated. The mRNA expression of MyD88, TLR4, NF-κB and IκB were estimated. Sinomenine treated rats significantly (p<0.001) suppressed the body weight and modulated the organ weight (hepatic, renal and heart). Sinomenine significantly (p<0.001) decreased the level of triacylglycerols (TG), low density lipoprotein cholesterol (LDL-c), total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-c) and augmented the level of high-density lipoprotein cholesterol (HDL-c). Sinomenine treatment also reduced the level of atherogenic index (TC/HDL-c and LDL-c/HDL-c). Sinomenine treatment decrease the ratio of HMG CoA/Mevalonate and level of collagen and total protein. Sinomenine significantly (p<0.001) altered the level of heart parameters, antioxidant parameters and inflammatory cytokines. Sinomenine significantly (p<0.001) reduced the expression of MyD88, TLR4, NF-κB and IκB. Taken together, sinomenine exhibited the protective effect against the atherosclerosis via alteration of TLR4/NF-κB signaling pathway.
Topics: Administration, Oral; Animals; Antioxidants; Atherosclerosis; Cholecalciferol; Cytokines; Diet, High-Fat; Inflammation; Inflammation Mediators; Lipid Metabolism; Male; Morphinans; NF-kappa B; Oxidative Stress; Phytotherapy; Rats, Sprague-Dawley; Signal Transduction; Sinomenium; Toll-Like Receptor 4; Rats
PubMed: 34866111
DOI: 10.5650/jos.ess21255 -
Scientific Reports Jan 2023Dengue virus (DENV) infection has increased worldwide, with over 400 million infections annually, and has become a serious public health concern. Several drug...
Dengue virus (DENV) infection has increased worldwide, with over 400 million infections annually, and has become a serious public health concern. Several drug candidates, new and repurposed, have failed to meet the primary efficacy endpoints. We have recently shown that Aqueous Extract of the stem of Cocculus hirsutus (AQCH) was effective in vitro and in vivo against DENV and was safe in humans. We now report that an active ingredient of AQCH, Sinococuline, protects against the antibody-mediated secondary-DENV infection in the AG129 mouse model. DENV infection markers were assessed, viz. serum viremia and vital organs pathologies-viral load, proinflammatory cytokines and intestinal vascular leakage. The treatment with Sinococuline at 2.0 mg/kg/day; BID (twice a day), was the most effective in protecting the severely DENV-infected AG129 mice. Also, this dose effectively reduced serum viremia and tissue-viral load and inhibited the elevated expression levels of proinflammatory cytokines (TNF-α and IL-6) in several vital organs. Based on these findings, it could be explored further for pre-clinical and clinical developments for the treatment of dengue.
Topics: Animals; Humans; Mice; Cocculus; Cytokines; Dengue Virus; Disease Models, Animal; Viremia; Morphinans
PubMed: 36658277
DOI: 10.1038/s41598-023-27927-3 -
Bioorganic & Medicinal Chemistry May 2011A novel series of homo- and heterodimeric ligands containing κ/μ agonist and μ agonist/antagonist pharmacophores joined by a 10-carbon ester linker chain were...
A novel series of homo- and heterodimeric ligands containing κ/μ agonist and μ agonist/antagonist pharmacophores joined by a 10-carbon ester linker chain were synthesized and evaluated for their in vitro binding affinity at κ, μ, and δ opioid receptors, and their functional activities were determined at κ and μ receptors in [(35)S]GTPγS functional assays. Most of these compounds had high binding affinity at μ and κ receptors (K(i) values less than 1nM). Compound 15b, which contains butorphan (1) at one end of linking chain and butorphanol (5) at the other end, was the most potent ligand in this series with binding affinity K(i) values of 0.089nM at the μ receptor and 0.073nM at the κ receptor. All of the morphinan-derived ligands were found to be partial κ and μ agonists; ATPM-derived ligands 12 and 11 were found to be full κ agonists and partial μ agonists.
Topics: Animals; Butorphanol; CHO Cells; Cricetinae; Cricetulus; Decanoates; Humans; Ligands; Morphinans; Protein Binding; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu
PubMed: 21482470
DOI: 10.1016/j.bmc.2011.03.052 -
The American Journal on Addictions 2009There is increasing evidence that the kappa-opiate receptor, in addition to the mu-opiate receptor, plays an important role in substance use pathophysiology and... (Review)
Review
There is increasing evidence that the kappa-opiate receptor, in addition to the mu-opiate receptor, plays an important role in substance use pathophysiology and behavior. As dopamine activity is upregulated through chronic substance use, kappa receptor activity, mediated through the peptide dynorphin, is upregulated in parallel. Dynorphin causes dysphoria and decreased locomotion, and the upregulation of its activity on the kappa receptor likely dampens the excitation caused by increased dopaminergic activity. This feedback mechanism may have significant clinical implications for treating drug dependent patients in various stages of their pathology.
Topics: Brain; Ethylketocyclazocine; Humans; Locomotion; Morphinans; Receptors, Opioid, kappa; Spiro Compounds; Substance-Related Disorders; Up-Regulation
PubMed: 19444730
DOI: 10.1080/10550490902925862 -
Medical Science Monitor : International... Jan 2021BACKGROUND This study aims to explore the effect of Sinomenine (SIN) on pregnancy outcomes of recurrent spontaneous abortion (RSA) in a mouse model. MATERIAL AND METHODS...
BACKGROUND This study aims to explore the effect of Sinomenine (SIN) on pregnancy outcomes of recurrent spontaneous abortion (RSA) in a mouse model. MATERIAL AND METHODS Thirty female CBA/J mice were allocated into 3 groups randomly, then mated with BALB/c mice (CBA/J×BALB/c) as normal-pregnancy group (n=10), or mated with DBA/2 mice (CBA/J×DBA/2) as RSA model (n=10), or CBA/J×DBA/2 mice treated with SIN as RSA+SIN group (n=10). The number of surviving and reabsorbed embryos in each group were counted on day 13.5 of gestation. The mouse serum was collected to determine the levels of interferon-γ (IFN)-γ and IL-4 by ELISA. Immunohistochemistry, qRT-PCR and immunoblotting were used to determine the location, mRNA and protein expressions of IFN-γ, IL-4, T-bet and GATA3 in the decidual and placental tissue. RESULTS In the RSA group, the amount of reabsorbed embryo was significantly higher than that in the normal-pregnancy group. However, SIN treatment showed a rescue effect on spontaneous abortion in RSA mice. IFN-γ, IL-4, T-bet, and GATA3 were all expressed in placental tissues and mainly located in the cytoplasm. The RSA group demonstrated higher expression levels of IFN-γ and T-bet than in the RSA+SIN and normal-pregnancy groups. Although RSA and RSA+SIN groups showed lower expression levels of IL-4 and GATA3 than in the normal-pregnancy group, there was no significant difference between RSA and RSA+SIN groups regarding IL-4 and GATA expression levels. CONCLUSIONS SIN treatment demonstrates a therapeutic effect on spontaneous abortion in RSA mice, possibly through regulating the balance of Th1/Th2 in maternal circulation and decidual tissues.
Topics: Abortion, Spontaneous; Animals; Decidua; Disease Models, Animal; Embryo, Mammalian; Female; GATA3 Transcription Factor; Interferon-gamma; Interleukin-4; Male; Mice; Morphinans; Placenta; Pregnancy; T-Box Domain Proteins; Th1-Th2 Balance
PubMed: 33390585
DOI: 10.12659/MSM.927709 -
British Journal of Clinical Pharmacology Jul 19881. Actions and interactions on performance and respiration of single intramuscular doses of 0.15 mg kg-1 nalbuphine and oral haloperidol twice daily for 2 days were... (Clinical Trial)
Clinical Trial
1. Actions and interactions on performance and respiration of single intramuscular doses of 0.15 mg kg-1 nalbuphine and oral haloperidol twice daily for 2 days were studied double-blind and cross-over in 12 healthy volunteers. 2. Objective measurements of performance (choice reaction, tracking, attention, flicker fusion, Maddox wing, digit symbol substitution) and respiratory function (minute volume, end-tidal carbon dioxide), and subjective assessments on visual analogue scales were done at baseline and 1 h, 2.5 h and 4 h after the injection of nalbuphine. Plasma concentrations of nalbuphine were estimated by radioreceptor ([3H]-dihydromorphine) assay, and those of prolactin and growth hormone by radioimmunoassay. 3. Nalbuphine affected digit substitution, reaction time, extraocular muscle balance and flicker recognition, and depressed respiration most clearly 1 and 2.5 h post injection. Motor skills were impaired only briefly. Haloperidol alone proved inert on performance but enhanced the decremental effects of nalbuphine on digit substitution and exophoria at 1 h. It did not interact with nalbuphine on the ventilatory function. 4. Plasma concentrations of nalbuphine expressed as morphine equivalents ranged from 5 to 52 ng ml-1, indicating considerable mu-opiate affinity. Treatment with haloperidol increased plasma prolactin moderately whilst nalbuphine raised it markedly 1 and 2.5 h post injection. Nalbuphine elevated plasma growth hormone at 1 h post injection only.
Topics: Adult; Clinical Trials as Topic; Double-Blind Method; Drug Interactions; Female; Haloperidol; Humans; Male; Morphinans; Nalbuphine; Neurosecretory Systems; Psychomotor Performance; Random Allocation; Respiration; Respiratory Function Tests
PubMed: 3060191
DOI: 10.1111/j.1365-2125.1988.tb03367.x -
Journal of the American Society For... Nov 2003In this study positive ESI tandem mass spectra of the [M + H]+ ions of morphinan alkaloids obtained using an ion trap MS were compared with those from a triple...
In this study positive ESI tandem mass spectra of the [M + H]+ ions of morphinan alkaloids obtained using an ion trap MS were compared with those from a triple quadrupole MS. This allows to assess the differences of the tandem-in-time versus the tandem-in-space principle, often hampering the development of ESI MS/MS libraries. Fragmentation pathways and possible fragment ion structures were discussed. In order to obtain elemental composition, accurate mass measurements were performed. According to the MS/MS fragmentation pathway, the investigated compounds can be grouped into 4 subsets: (1) morphine and codeine, (2) morphinone, codeinone, and neopinone, (3) thebaine and oripavine, (4) salutaridine and salutaridinol. Salutaridinol-7-O-acetate shows a different fragmentation behavior because of the favored loss of acetic acid. Although most fragment ions occur in both ion trap and triple quad tandem mass spectra, some are exclusively seen in either type. For triple quad, quadrupole time-of-flight and FT-ICR MS/MS, the base peak of morphine results from an ion at m/z 165 that contains neither nitrogen nor oxygen. This ion is not found in ion trap MS/MS, but in subsequential MS3 and MS4.
Topics: Fourier Analysis; Indicators and Reagents; Morphinans; Morphine Derivatives; Spectrometry, Mass, Electrospray Ionization
PubMed: 14597116
DOI: 10.1016/S1044-0305(03)00539-7 -
The AAPS Journal Jan 2021Oxycodone is an opioid analgesic that is commonly prescribed to pregnant women to treat moderate-to-severe pain. It has been shown to cross the placenta and distribute...
Oxycodone is an opioid analgesic that is commonly prescribed to pregnant women to treat moderate-to-severe pain. It has been shown to cross the placenta and distribute to the fetus. Oxycodone is mainly metabolized by CYP3A4 in the adult liver. Since CYP3A7 is abundantly expressed in the fetal liver and has overlapping substrate specificity with CYP3A4, we hypothesized that the fetal liver may significantly limit fetal exposure to oxycodone. This study showed that oxycodone is metabolized by CYP3A7 to noroxycodone in fetal liver microsomes (FLMs). The measured CYP3A7 expression was 191-409 pmol/mg protein in 14 FLMs, and an intersystem extrapolation factor (ISEF) for CYP3A7 was 0.016-0.066 in the panel of fetal livers using 6β-OH-testosterone formation as the probe reaction. Noroxycodone formation in the fetal liver was predicted from formation rate by recombinant CYP3A7, CYP3A7 expression level and the established ISEF value with average fold error of 1.25. Based on the intrinsic clearance of oxycodone measured in FLM, the fetal hepatic clearance (CL) at term was predicted to be 495 (range: 66.4-936) μL/min, a value that is > 99% lower than the predicted adult liver CL. The predicted fetal hepatic extraction ratio was 0.0019 (range: 0.00003-0.0036). These results suggest that fetal liver metabolism does not quantitatively contribute to the total systemic clearance of oxycodone in pregnant women nor does it provide a barrier for limiting fetal exposure to oxycodone. Additionally, since CYP3A7 forms noroxycodone, an inactive metabolite, the metabolism in the fetal liver is unlikely to affect fetal opioid activity.
Topics: Adult; Cytochrome P-450 CYP3A; Enzyme Assays; Female; Fetus; Hepatobiliary Elimination; Humans; Liver; Male; Maternal-Fetal Exchange; Microsomes, Liver; Morphinans; Oxycodone; Placenta; Pregnancy; Primary Cell Culture; Recombinant Proteins
PubMed: 33438174
DOI: 10.1208/s12248-020-00537-x -
ELife Feb 2021Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants...
Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here, we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with , to rationally design novel mixed mu (MOR) and kappa (KOR) opioid receptor agonists with reduced arrestin signaling. Analysis of structure-activity relationships for new analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) as key for modulation of arrestin recruitment to both MOR and KOR. The lead compounds, displayed MOR/KOR Gi-partial agonism with diminished arrestin signaling, showed efficient analgesia with attenuated liabilities, including respiratory depression and conditioned place preference and aversion in mice. The findings validate a novel structure-inspired paradigm for achieving beneficial in vivo profiles for analgesia through different mechanisms that include bias, partial agonism, and dual MOR/KOR agonism.
Topics: Amino Acid Motifs; Analgesics; Animals; Binding Sites; Ligands; Male; Mice; Mice, Inbred C57BL; Molecular Docking Simulation; Morphinans; Receptors, Opioid, kappa; Receptors, Opioid, mu; Structure-Activity Relationship
PubMed: 33555255
DOI: 10.7554/eLife.56519