Salutaridine

Specific optical rotation: -98 deg at 20 °C/D (c = 0.55 g/100 mL CH3OH). UV max (methanol): 276, 240 (log e 3.76, 4.24) /(-)-Salutaridine/

Specific optical rotation: +114 deg ay 12 °C/D (c = 0.5 in methanol)

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1540(SRC), determined from a structure estimation method(2), indicates that salutaridine is expected to have low mobility in soil(SRC). The estimated pKa of salutaridine is 7.41(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of the cation from moist soil is not expected because cations do not volatilize(SRC). Volatilization of neutral salutaridine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 8.1X10-16 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Salutaridine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.7X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2016).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1540(SRC), determined from a structure estimation method(2), indicates that salutaridine is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 7.41(3) indicates salutaridine will exist partially in the cation form at pH values of 5 to 9 and, therefore, volatilization of the cation from water surfaces is not expected to be an important fate process(SRC). Volatilization of neutral salutaridine from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 8.1X10-16 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). Salutaridine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from an estimated log Kow of 0.96(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation data in water were not available(SRC, 2016).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), salutaridine, which has an estimated vapor pressure of 1.7X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase salutaridine may be removed from the air by wet and dry deposition(SRC). Salutaridine contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

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.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of salutaridine can be estimated to be 1540(SRC). According to a classification scheme(2), this estimated Koc value suggests that salutaridine is expected to have low mobility in soil. The estimated pKa of salutaridine is 7.41(3), indicating that this compound will exist partially in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

An estimated BCF of 3 was calculated in fish for salutaridine(SRC), using an estimated log Kow of 0.96(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low.

An estimated pKa of 7.41(1) indicates salutaridine will exist partially in the cation form at pH values of 5 to 9 and, therefore, volatilization from water and moist soil surfaces of the cation is not expected to be an important fate process(SRC). The Henry's Law constant for salutaridine is estimated as 8.1X10-16 atm-cu m/mole(SRC) using a fragment constant estimation method(2). This Henry's Law constant indicates that neutral salutaridine is expected to be essentially nonvolatile from water and moist soil surfaces(3). Salutaridine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.7X10-9 mm Hg(SRC), determined from a fragment constant method(2).

/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.

/ALTERNATIVE and IN VITRO TESTS/ The alkaloid 5,6,8,14-tetradehydro-4-hydroxy-3, 6-dimethoxy-17-methyl-morphinan-7-one[+/-)-salutaridine) was found to possess (3)H-gamma-aminobutyric acid ((3)H-GABA) displacing activity (IC50 less than 1 mumol/L) in rat brain synaptic membranes. The enhancement of specific (3)H-diazepam binding by increasing concentration of (+/-)-salutaridine follows a maximum curve indicating (+/-)-salutaridine to be a partial agonist at the GABA/benzodiazepine receptor complex.

/ALTERNATIVE and IN VITRO TESTS/ G-protein activation by receptors is generally measured using (35)S-GTPgammaS binding assays in cell membranes and cannot be well assessed in intact cells. We have recently developed a fluorescence resonance energy transfer (FRET)-based approach to monitor G(i)-protein activation in living cells. Here we report that this technique can be used to determine structure-activity relationships of receptor agonists in intact cells. We have recently shown that morphine is biosynthesized de novo by mammals via a multistep pathway different from that in plants. However, the pharmacological properties of morphine precursors are poorly understood. Here, we directly monitored mu-opioid receptor (MOR)-mediated G(i)-protein activation in living cells by FRET and validated this method with classical GTPgammaS binding assays. Receptor binding studies and FRET measurements demonstrated that several (R)-configurated morphine precursors such as (R)-reticuline, salutaridine, salutaridinol, thebaine, and codeine were partial MOR agonists. Some closer precursors such as oripavine, codeinone, and morphinone activated G(i)-proteins as strongly as morphine, but with slightly lower potencies. The more distant the precursors were positioned in the pathway with respect to morphine, the less efficient and potent they were at MOR. Comparison of pharmacological properties of close morphine precursors and concentrations in which they occur in animal tissues suggests that they might activate MOR signaling under physiological conditions. Taken together, our data indicate that FRET-based assays of G-protein activation can serve to determine the abilities of compounds to activate G-protein signaling directly and in living cells.

/ALTERNATIVE and IN VITRO TESTS/ Two new aporphine alkaloids, isofiliformine (1) and cassythic acid (3), along with 22 known compounds were isolated from whole herb of Cassytha filiformis. Cassythic acid (3), cassythine (4), neolitsine (7), and dicentrine (8) had potent vasorelaxing effects on precontracted rat aortic preparations with mean IC 50 values between 0.08 and 2.48 microM. Compounds 1, 1,2-methylenedioxy-3,10,11-trimethoxyaporphine (2), (-)- O-methylflavinatine (10), (-)-salutaridine (11), isohamnetin-3- O-beta-glucoside, and isohamnetin-3- O-rutinoside exerted moderate vessel-relaxing activities with IC 50 values from 16.50 to 32.81 uM at the test concentrations.

Salutaridine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Salutaridine contains chromophores that absorb at wavelengths >290 nm(1) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Occupational exposure to salutaridine may occur through dermal contact with this compound at workplaces where salutaridine is extracted or used. Use data indicate that the general population is not likely to be exposed to salutaridine. (SRC)

Salutaridine's extraction and use as an intermediate in the production of opiates may result in its release to the environment through various waste streams. Salutaridine is a constituent of plants in the family Papaveraceae. If released to air, an estimated vapor pressure of 1.7X10-9 mm Hg at 25 °C indicates salutaridine will exist solely in the particulate phase in the atmosphere. Particulate-phase salutaridine will be removed from the atmosphere by wet and dry deposition. Salutaridine contains chromophores that absorb at wavelengths >290 nm and, therefore, may be susceptible to direct photolysis by sunlight. If released to soil, salutaridine is expected to have low mobility based upon an estimated Koc of 1540. The estimated pKa of salutaridine is 7.41, indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts. Volatilization from moist soil of cationic salutaridine is not expected because cations do not volatilize. Volatilization of neutral salutaridine from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 8.1X10-16 atm-cu m/mole. Salutaridine is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation data in soil or water were not available. If released into water, salutaridine is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated pKa and Henry's Law constant. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure to salutaridine may occur through dermal contact with this compound at workplaces where salutaridine is extracted or used. Use data indicate that the general population is not likely to be exposed to salutaridine. (SRC)

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.

Isolated from various species of Croton and Papaver.

Isolated from Nandina domestica Thunb

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 narcotic analgesics such as morphine and codeine.