It has been firmly established that humans excrete a small but steady amount of the isoquinoline alkaloid morphine in their urine. It is unclear whether it is of dietary or endogenous origin. There is no doubt that a simple isoquinoline alkaloid, tetrahydropapaveroline (THP), is found in human and rodent brain as well as in human urine. This suggests a potential biogenetic relationship between both alkaloids. Unlabeled THP or [1,3,4-D(3)]-THP was injected intraperitoneally into mice and the urine was analyzed. This potential precursor was extensively metabolized (96%). Among the metabolites found was the phenol-coupled product salutaridine, the known morphine precursor in the opium poppy plant. Synthetic [7D]-salutaridinol, the biosynthetic reduction product of salutaridine, injected intraperitoneally into live animals led to the formation of [7D]-thebaine, which was excreted in urine. [N-CD(3)]-thebaine was also administered and yielded [N-CD(3)]-morphine and the congeners [N-CD(3)]-codeine and [N-CD(3)]-oripavine in urine. These results show for the first time that live animals have the biosynthetic capability to convert a normal constituent of rodents, THP, to morphine. Morphine and its precursors are normally not found in tissues or organs, presumably due to metabolic breakdown. Hence, only that portion of the isoquinoline alkaloids excreted in urine unmetabolized can be detected. Analysis of urine by high resolution-mass spectrometry proved to be a powerful method for tracking endogenous morphine and its biosynthetic precursors.
Endogenous codeine and morphine were identified in rat brain by immunological determination following HPLC. To demonstrate occurrence of a biosynthetic pathway to morphine in mammals similar to that used by the poppy plant, (+)-salutaridine, (-)-thebaine, and (-)-codeine were administered to rats intravenously. These compounds, which are intermediates in the synthesis of morphine in Papaver somniferum, caused a marked increase in the codeine and morphine levels in rat tissues. This provides evidence for a biosynthetic pathway to morphine in mammalians.
Microsomal preparations isolated from differentiated Papaver somniferum plants or from a thebaine-producing cell suspension culture catalyzed the conversion of (R)-reticuline to salutaridine. This enzyme system is strictly dependent on NADPH as a reducing cofactor, on molecular oxygen, and on (R)-configurated reticuline. Cytochrome P-450 inhibitors such as naphthoquinones, prochloraz, ancymidole and carbon monoxide (in darkness but not in light) inhibit this phenol coupling reaction, suggesting that the enzyme is a cytochrome P-450-dependent oxidase. This enzyme system occurs in roots, shoots and capsules of the poppy plant but not in latex. Salutaridine, the key intermediate in morphine biosynthesis, is formed from (R)-reticuline by a regio- and stereoselective para-ortho oxidative coupling catalyzed by this microsomal cytochrome P-450 enzyme. Claims of another enzyme system reported in the literature previously are being refuted.
IDENTIFICATION AND USE: Salutaridine is a morphinane alkaloid from the opium poppy, in which the 5,6,8,14-tetradehydromorphinan-7-one skeleton is substituted at position 4 by a hydroxyl group, positions 3 and 6 by methoxy groups and position N17 by a methyl group. An intermediate in the biosynthesis of CNS depressant analgesics such as morphine and codeine. HUMAN EXPOSURE AND TOXICITY: There are no data available. ANIMAL STUDIES: Inhibited receptor activator of nuclear factor-kappaB ligand-induced differentiation of mouse bone marrow-derived macrophages into multinucleated osteoclasts. Salutaridine exerted moderate vessel-relaxing activities on precontracted rat aortic preparation.
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) or lorazepam (Ativan) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
/ALTERNATIVE and IN VITRO TESTS/ A phytochemical investigation for the rhizome extract from Sinomenium acutum (Menispermaceae) resulted in the isolation of several active principles responsible for the anti-osteoclastogenic property of the extract, together with related isoquinoline alkaloids (1-13) including two new compounds, 1 and 2. Among isolated compounds, salutaridine (7), dauricumine (10), cheilanthifoline (12), and dauriporphine (13) were observed to give significant inhibitions on receptor activator of nuclear factor-kappaB ligand-induced differentiation of mouse bone marrow-derived macrophages into multinucleated osteoclasts, respectively. The chemical structures of two newly isolated compounds, 1 and 2 were established as 8-demethoxycephatonine (1) and 7(R)-7,8-dihydrosinomenine (2), by spectroscopic analyses including 2D NMR experiments.
[EN] SYNTHESIS OF MORPHINE AND RELATED DERIVATIVES<br/>[FR] SYNTHÈSE DE LA MORPHINE ET DE DÉRIVÉS ASSOCIÉS
申请人：UNIV TEXAS
公开号：WO2010132570A1
公开（公告）日：2010-11-18
The present invention relates to methods for the synthesis of galanthamine, morphine, intermediates, salts and derivatives thereof, wherein the starting compound is biphenyl.
本发明涉及一种合成迷迭香碱、吗啡、中间体、盐和衍生物的方法，其中起始化合物为联苯。
[EN] COMPOSITIONS AND METHODS FOR MAKING NOSCAPINE AND SYNTHESIS INTERMEDIATES THEREOF<br/>[FR] COMPOSITIONS ET PROCÉDÉS DE FABRICATION DE NOSCAPINE ET D'INTERMÉDIAIRES DE SYNTHÈSE DE CELLE-CI
申请人：EPIMERON INC
公开号：WO2015021561A1
公开（公告）日：2015-02-19
Methods for the manufacture of the therapeutic chemical compound noscapine and noscapine synthesis intermediates comprising contacting a noscapine pathway precursor selected from a first canadine derivative, a first papaveroxine derivative and narcotine hemiacetal with at least one of the enzymes selected from the group CYP82Y1, CYP82X1, AT1, CYP82X2, OMT, CXE1 and NOS.
Rat CYP2D2, not 2D1, is functionally conserved with human CYP2D6 in endogenous morphine formation
作者：Nadja Grobe、Toni M. Kutchan、Meinhart H. Zenk
DOI：10.1016/j.febslet.2012.05.021
日期：2012.6.21
codeine. In addition, CYP2D2 incubated with (R)‐reticuline generated four products corytuberine, pallidine, salutaridine and isoboldine while rat CYP2D1 was completely inactive. This intramolecular phenol‐coupling reaction follows the same mechanism as observed for CYP2D6. Michaelis–Menten kinetic parameters revealed high catalytic efficiencies for rat CYP2D2. These findings suggest a critical evaluation
Demethylation of Reticuline and Derivatives Thereof with Fungal Cytochrome P450
申请人：River Stone Biotech APS
公开号：US20210230655A1
公开（公告）日：2021-07-29
The invention relates to recombinant host cells that expresses one or more genes encoding a cytochrome P450 enzyme capable of N-demethylating and/O-demethylating reticuline and/or derivatives thereof, and also methods of producing a N-demethylated and/or O-demethylated reticuline and/or derivatives thereof, comprising cultivating the recombinant host of the invention in a culture medium under conditions in which the one or more genes encoding the cytochrome P450 enzymes is/are expressed. The reticuline and derivatives thereof are useful for providing access to naturally unavailable and chemically difficult-to-produce starting materials for opioids.
Plants of the order Ranunculales, especially members of the species Papaver, accumulate a large variety of benzylisoquinoline alkaloids with about 2,500 structures. But only the opium poppy, Papaver somniferum, and Papaver setigerum, are able to produce morphinan alkaloids such as the analgesic morphine or the antitussive codeine. We investigated the molecular basis for this exceptional biosynthetic capability by comparison of alkaloid profiles with gene expression profiles between sixteen different Papaver species and identified one cDNA which exhibits very similar expression pattern to previously isolated cDNAs coding for enzymes in benzylisoquinoline biosynthesis and which showed the highest amino acid identity to reductases in menthol biosynthesis. When expressed, the protein encoded by this cDNA reduced the keto group of salutaridine yielding salutaridinol, an intermediate in morphine biosynthesis. The stereoisomer epi-salutaridinol was not formed. The encoded protein was identified as salutaridine reductase (SalR; EC 1.1.1.248) and it was found to belongs to the family of the short chain dehydrogenases / reductases.
