2-Arachidonyl glyceryl ether (2-AGE, Noladin ether) is a putative

endocannabinoid Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...

discovered by Lumír Hanuš and colleagues at the

Hebrew University of Jerusalem The Hebrew University of Jerusalem (HUJI; he, הַאוּנִיבֶרְסִיטָה הַעִבְרִית בִּירוּשָׁלַיִם) is a public research university based in Jerusalem, Israel. Co-founded by Albert Einstein and Dr. Chaim Weiz ...

, Israel. It is an

ether In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...

formed from the alcohol analog of arachidonic acid and

glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...

. Its isolation from

porcine The pig (''Sus domesticus''), often called swine, hog, or domestic pig when distinguishing from other members of the genus '' Sus'', is an omnivorous, domesticated, even-toed, hoofed mammal. It is variously considered a subspecies of ''Sus ...

brain and its structural elucidation and synthesis were described in 2001.

Discovery

Lumír Hanuš, Saleh Abu-Lafi, Ester Fride, Aviva Breuer, Zvi Vogel, Deborah E. Shalev, Irina Kustanovich, and

Raphael Mechoulam Raphael Mechoulam ( he, רפאל משולם, bg, Рафаел Мешулам; born 5 November 1930) is an Israeli organic chemist and professor of Medicinal Chemistry at the Hebrew University of Jerusalem in Israel. Mechoulam is best known for h ...

found the endogenous

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the

cannabinoid receptor type 1 Cannabinoid receptor type 1 (CB1), also known as cannabinoid receptor 1, is a G protein-coupled cannabinoid receptor that in humans is encoded by the ''CNR1'' gene. The human CB1 receptor is expressed in the peripheral nervous system and central ...

(CB1) in 2000. The discovery was 100 gram of porcine brain, (approximately a single brain) was added to a mixture of 200 mL of

chloroform Chloroform, or trichloromethane, is an organic compound with chemical formula, formula Carbon, CHydrogen, HChlorine, Cl3 and a common organic solvent. It is a colorless, strong-smelling, dense liquid produced on a large scale as a precursor to ...

and 200 mL of

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is a ...

and mixed in a

laboratory A laboratory (; ; colloquially lab) is a facility that provides controlled conditions in which scientific or technological research, experiments, and measurement may be performed. Laboratory services are provided in a variety of settings: physicia ...

blender A blender (sometimes called a mixer or liquidiser in British English) is a kitchen appliance, kitchen and laboratory appliance used to mix, crush, purée or emulsion, emulsify food and other substances. A stationary blender consists of a blender ...

for 2 minutes. 100 mL of Water was then added, and the mixing process continued for another minute. After this, the mixture was filtered. Two layers then formed and the layer of water-methanol was separated and evaporated when

pressure Pressure (symbol: ''p'' or ''P'') is the force applied perpendicular to the surface of an object per unit area over which that force is distributed. Gauge pressure (also spelled ''gage'' pressure)The preferred spelling varies by country and e ...

was reduced. Synaptosomal membranes were prepared from 250g of the brains of Sabra male rats. A

Hewlett Packard The Hewlett-Packard Company, commonly shortened to Hewlett-Packard ( ) or HP, was an American multinational information technology company headquartered in Palo Alto, California. HP developed and provided a wide variety of hardware components ...

G 1800B GCD system that has a HP-5971 GC with electron ionization detector was used.

Production

The production of the endocannabinoid is enhanced in normal, but not in endothelium-denuded rat aorta on reacting with

carbachol Carbachol, also known as carbamylcholine and sold under the brand name Miostat among others, is a cholinomimetic drug that binds and activates acetylcholine receptors. Thus it is classified as a cholinergic agonist. It is primarily used for va ...

, a

parasympathomimetic drug A parasympathomimetic drug, sometimes called a cholinomimetic drug or cholinergic receptor stimulating agent, is a substance that stimulates the parasympathetic nervous system (PSNS). These chemicals are also called cholinergic drugs because ace ...

. It potently reduces

blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...

in rats and may represent an

endothelium The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vesse ...

-derived

hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dias ...

factor. 2-Arachidonyl glyceryl ether's structure can be determined by

mass spectrometry Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is use ...

and

Rutherford backscattering spectrometry Rutherford backscattering spectrometry (RBS) is an analytical technique used in materials science. Sometimes referred to as high-energy ion scattering (HEIS) spectrometry, RBS is used to determine the structure and composition of materials by mea ...

. It was confirmed by comparison with a synthetic sample of the

. It binds to the

Cannabinoid receptor type 1 Cannabinoid receptor type 1 (CB1), also known as cannabinoid receptor 1, is a G protein-coupled cannabinoid receptor that in humans is encoded by the ''CNR1'' gene. The human CB1 receptor is expressed in the peripheral nervous system and central ...

(''Ki = 21.2 ± 0.5 nM''), which causes sedation,

hypothermia Hypothermia is defined as a body core temperature below in humans. Symptoms depend on the temperature. In mild hypothermia, there is shivering and mental confusion. In moderate hypothermia, shivering stops and confusion increases. In severe h ...

, intestinal immobility, and mild antinociception in

mice A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

. The endocannabinoid exhibits Ki values of 21.2 nM and >3 μM at the Cannabinoid receptor type 1 and the peripheral cannabinoid receptors."2-Arachidonyl Glycerol ether · Noladin; 2-AG ether (CAS 222723-55-9) , , Cayman Chemical"
Cayman Chemical. Retrieved 2011-05-29. The presence of 2-AGE in body tissue is disputed. Although a research group from

Teikyo University is a private university headquartered in the Itabashi ward of Tokyo, Japan. It was established in 1931 as Teikyo Commercial High School (帝京商業高等学校). It became Teikyo University in 1966. It is part of Teikyo Group, a multinational ...

Kanagawa is a Prefectures of Japan, prefecture of Japan located in the Kantō region of Honshu. Kanagawa Prefecture is the List of Japanese prefectures by population, second-most populous prefecture of Japan at 9,221,129 (1 April 2022) and third-dens ...

, Japan could not detect it in the brains of mice, hamsters, guinea-pigs or pigs, two other research groups successfully detected it in animal tissues.

Pharmacology

2-AGE binds with a K_i of 21 nM to the CB₁ receptor and 480 nM to the CB₂ receptor. It shows agonistic behaviour on both receptors and is a partial agonist for the

TRPV1 The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the ''TRPV1'' gene. It was the first isolated member of th ...

channel. After binding to CB2 receptors it inhibits

adenylate cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

and stimulates ERK-MAPK and regulates calcium transients. In comparison to 2-arachidonoyl glycerol, noladin is metabolically more stable resulting in a longer half-life. It lowers

Intraocular pressure Intraocular pressure (IOP) is the fluid pressure inside the eye. Tonometry is the method eye care professionals use to determine this. IOP is an important aspect in the evaluation of patients at risk of glaucoma. Most tonometers are calibrated t ...

, increases the uptake of GABA in the

globus pallidus The globus pallidus (GP), also known as paleostriatum or dorsal pallidum, is a subcortical structure of the brain. It consists of two adjacent segments, one external, known in rodents simply as the globus pallidus, and one internal, known in rod ...

of rats and is neuroprotective by binding to and activation of

PPAR In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the reg ...

α.

References

External links

Commercial supplier of Noladin ether
{{DEFAULTSORT:Arachidonyl glyceryl ether, 2- CB1 receptor agonists CB2 receptor agonists Lipids Endocannabinoids Arachidonyl compounds Glycerol ethers Diols

Discovery

Production

Pharmacology

See also

References

External links