Salutaridine

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)