Tritium-labeled 2-arachidonoyl-[1,3-3h]-glycerol

FIELD: organic chemistry, labeled compounds.

SUBSTANCE: invention relates to new tritium-labeled 2-arachidonoyl-[1,3-3H]-glycerol of the formula: CH3-(CH2)4-(CH=CHCH2)4-(CH2)2-COOCH-(C3HHOH)2 able to bind and activate cannabinoid receptors. This compound can be used in analytical, bioorganic chemistry, biochemistry and applied medicine.

EFFECT: valuable properties of compound.

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The invention relates to the field of organic chemistry and can find application in analytical chemistry, Bioorganic chemistry, biochemistry and applied medicine.

In the study of metabolism and mechanism of action of physiologically active compounds necessary for their labeled counterparts.

It is known that substitution of atoms of compounds for their labeled counterparts does not change any properties of the original compound (E.A. Evans - Tritium and its compounds London Butterworths, 1974, p.48).

Known 2-arachidonoylglycerol formula:


This compound is able to bind and activate cannabinoid receptors (Sugiura T., Kondo, S., Kishimoto, S., Miyashita T., Nakane, S., Kodaka T., Suhara y, Takayama h, Waku K. J. Biol. Chem. 2000. V.275. P.605-612), which makes the actual research into the mechanisms of its action and metabolism. Such research is only effective when using tritium-labeled such compounds, in which the label is to be kept in glycerol residue of the molecule. This requirement is due to the fact that resulting from the hydrolysis of 2-arachidonoylglycerol arachidonic acid capable of being converted into other biologically active substances (for example, oxylipin) or quickly incorporated into membrane lipids. When using labeled by arachidonic acid 2-Ara is ideolgical, these transformations released label significantly distort the picture of the behaviour of the 2-arachidonoylglycerol. In addition, the study of the metabolism of 2-arachidonoylglycerol important certainty the position of the tritium label.

To date 2-arachidonoyl-[1,3-3H]-glycerol is not described.

The technical result achieved by the present invention, is expanding the range selectively tritium-labeled analogs of the physiologically active compounds.

Achieved the specified technical result obtaining tritium-labeled 2-arachidonoyl-[1,3-3H]-glycerol of the formula:


The following is an example implementation of the invention.

Example 1.

a) Synthesis of tritium-labeled 1,3-dibenzyl-[1,3-3H]-glycerol.

In one of the two sections 2 sectional reaction vials were placed catalysts: 12 mg PdO, 11 mg of 5% PdO/Al2About3. In another section was placed 110 μl solution of 2 mg of dibenzalacetone in a mixture of dioxane with triethylamine (10:1) and frozen with liquid nitrogen. Then the reaction, the ampoule was evacuated to a pressure of 0.1 PA, filled with gaseous tritium to pressure 333 hPa. When heated sections, which were catalysts (70°10 min), were recovering palladium oxide with images is of isotopomeres water, which condense in section cooled by liquid nitrogen. Then remove the excess tritium degassing. Cooling is transferred to the section containing catalysts, and poured into it a solution of benzyloxyaniline with isotopomeres water. Section ampoules containing the reaction mixture was sealed and kept in a thermostat at 115°C for 60 minutes Then the vial was again frozen with liquid nitrogen, cracked, solvents and isotope-labeled water is kept in a special receiver, and the residue was dissolved in 1 ml of methanol. The catalysts were filtered off, washed with methanol (5×1 ml), labile tritium was removed by evaporation of the filtrate with methanol (5×1 ml). The residue containing about 1 mg of labeled dibenzalacetone, were treated for 20 min with 2 ml of methanolic solution of sodium borohydride (1 mg/ml). Recovery was complete. The chromatographic purification and analysis was performed as follows. TLC was carried out on silicagel records in the system: chloroform-ether (4:1) Rf1,3-dibenzylamino - 0.59, Rf- dibenzylideneacetone - 0.86; chloroform-ether (10:1) Rf1,3-dibenzylamino - 0.30, Rf- dibenzylideneacetone - 0.66. HPLC was performed on a column of Inertsil ODS2, 5 μm, 4.6×125 mm, v - 1.0 ml/min, in the system methanol-water (70:30), retention time - 5.37 min (dibenzylideneacetone) and 5.61 min (1,3-dibenzylamino); in the system acetone is home to the thrill-water (50:50), retention time - 6.03 min (dibenzylideneacetone) and 8.55 min (1,3-dibenzylamino); column Kromasil C18, 7 μm, 4×150 mm, v - 0.8 ml/min, acetonitrile : water (50:50), retention time - 11.38 min (dibenzylideneacetone); column Kromasil C18, 7 μm, 4×150 mm, v - 0.8 ml/min, methanol-chloroform (90:10), retention time - 2.41 min (1,3-dibenzylamino). After chromatographic purification the release of tritium-labeled 1,3-dibenzyl-[1,3-3H]-glycerol (40%), molar radioactivity of drug - 55-59 CI/mmol.

b) Synthesis of tritium-labeled 2-arachidonoyl-1,3-dibenzyl-[1,3-3H]-glycerol is carried out by condensation of foramerica arachidonic acid with 1,3-dibenzyl-[1,3-3H]-glycerol. Floramite arachidonic acid was obtained by treatment of arachidonic acid cyanouroptera in the presence of pyridine in absolute acetonitrile; the ratio of the acid-cinortele-pyridine 2 mg: 0,9 µg:1.0 g; reaction time 1.5 h the Reaction foramerica arachidonic acid with 1,3-dibenzyl-[1,3-3H]-glycerol (0.7 mg) conducted in the presence of dimethylaminopyridine (2 mg) in acetonitrile (0.3 ml), for 24 hours of the Release of labeled 2-arachidonoyl-1,3-dibenzyl-[1,3-3H]-glycerol per participant in the reaction of the labeled reagent is 50-70%.

a) 2-Arachidonoyl-[1,3-3H]-glycerol was obtained after removal of the protective groups with 2-arachidonoyl-1,3-dibenzyl-[1,3-3 H]-glycerol. A solution of 2-arachidonoyl-1,3-dibenzyl-[1,3-3H]-glycerol (1 mg) in methylene chloride was treated in the atmosphere of inert gas with a solution of bromethalin (0.58 M) during the day. The product was extracted by ethyl acetate. The yield of 2-arachidonoyl-[1,3-3H]-glycerol per participant in the reaction of the labeled reagent 40-50% with a molar radioactivity 45-50 CI/mmol.

Cleaning and analysis was performed by HPLC on columns Inertsil ODS2 and Kromasil C18in water-methanol and water and the combined acetonitrile systems using appropriate standards. For receiving and processing the chromatographic data system was used "Multichrome" (CJSC "ampersand character", Russia) based on IBM PC/AT. Radioactivity was measured by scintillation counter with an efficiency of registration of tritium 30% in dioxane scintillator.

The thus obtained new tritium-labeled physiologically active compound.

Tritium-labeled 2-arachidonoyl-[1,3-3H]-glycerol of formula

CH3(CH2)4(CH=SNSN2)4(CH2)2SOON (3NON)2.


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