2-Arachidonyl glyceryl ether
Encyclopedia
2-Arachidonyl glyceryl ether (2-AGE, Noladin ether) is a putative endocannabinoid discovered by Lumír Hanuš and colleagues at the Hebrew University of Jerusalem
, Israel. Its isolation from porcine brain and its structural elucidation and synthesis were described in 2001.
found the endogenous agonist
of the cannabinoid receptor type 1
(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
and 200 mL of methanol
and mixed in a laboratory
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
was reduced. Synaptosomal membranes were prepared from 250g of the brains of Sabra male rats. A Hewlett Packard G 1800B GCD system that has a HP-5971 GC with electron ionization
detector was used.
on reacting with carbachol
, an parasympathomimetic drug. It potently reduces blood pressure
in rats
and may represent an endothelium
-derived hypotension
factor.
2-Arachidonyl glyceryl ether's structure can be determined by mass spectrometry
and Rutherford backscattering spectrometry
. It was confirmed by comparison with a synthetic sample
of the endocannabinoid. It binds to the Cannabinoid receptor type 1
(Ki = 21.2 ± 0.5 nM), which causes sedation
, hypothermia
, intestinal immobility
, and mild antinociception in mice
. The endocannabinoid exhibits Ki values of 21.2 nM and >3 µM at the Cannabinoid receptor type 1 and the peripheral cannabinoid receptors.
The presence of 2-AGE in body tissue is disputed. Although a research group from Teikyo University
, Kanagawa, 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.
channel. After binding to CB2 receptors it inhibits adenylate cyclase
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
, increases the uptake of GABA
in the globus pallidus
of rats and is neuroprotective by binding to and activation of PPARα.
Hebrew University of Jerusalem
The Hebrew University of Jerusalem ; ; abbreviated HUJI) is Israel's second-oldest university, after the Technion – Israel Institute of Technology. The Hebrew University has three campuses in Jerusalem and one in Rehovot. The world's largest Jewish studies library is located on its Edmond J...
, Israel. Its isolation from porcine 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 MechoulamRaphael Mechoulam
Raphael Mechoulam is an Israeli professor of Medicinal Chemistry and Natural Products at the Hebrew University of Jerusalem in Israel...
found the endogenous agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
of the cannabinoid receptor type 1
Cannabinoid receptor type 1
The cannabinoid receptor type 1, often abbreviated to CB1, is a G protein-coupled cannabinoid receptor located in the brain. It is activated by endocannabinoid neurotransmitters including anandamide and by the compound THC, found in the psychoactive drug cannabis.-Expression:The CB1 receptor is...
(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
Chloroform is an organic compound with formula CHCl3. It is one of the four chloromethanes. The colorless, sweet-smelling, dense liquid is a trihalomethane, and is considered somewhat hazardous...
and 200 mL of methanol
Methanol
Methanol, also known as methyl alcohol, wood alcohol, wood naphtha or wood spirits, is a chemical with the formula CH3OH . It is the simplest alcohol, and is a light, volatile, colorless, flammable liquid with a distinctive odor very similar to, but slightly sweeter than, ethanol...
and mixed in a laboratory
Laboratory
A laboratory is a facility that provides controlled conditions in which scientific research, experiments, and measurement may be performed. The title of laboratory is also used for certain other facilities where the processes or equipment used are similar to those in scientific laboratories...
blender
Blender
A blender is a kitchen appliance for chopping or liquefying food.Blender may also refer to:Media:* Blender , a music-themed magazine* Blender , a free and open-source software program for 3D modeling, animation, and rendering...
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
Pressure is the force per unit area applied in a direction perpendicular to the surface of an object. Gauge pressure is the pressure relative to the local atmospheric or ambient pressure.- Definition :...
was reduced. Synaptosomal membranes were prepared from 250g of the brains of Sabra male rats. A Hewlett Packard G 1800B GCD system that has a HP-5971 GC with electron ionization
Electron ionization
Electron ionization is an ionization method in which energetic electrons interact with gas phase atoms or molecules to produce ions...
detector was used.
Production
The production of in the endocannabinoid is enhanced in normal, but not in endothelium-denuded rat aortaEndothelium-derived relaxing factor
Endothelium-derived relaxing factor is produced and released by the endothelium to promote smooth muscle relaxation. The best-characterized is nitric oxide . Some sources equate EDRF and nitric oxide....
on reacting with carbachol
Carbachol
Carbachol , also known as carbamylcholine, is a drug that binds and activates the acetylcholine receptor. Thus it is classified as a cholinergic agonist. It is primarily used for various ophthalmic purposes, such as for treating glaucoma, or for use during ophthalmic surgery...
, an parasympathomimetic drug. It potently reduces blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
in rats
Rat
Rats are various medium-sized, long-tailed rodents of the superfamily Muroidea. "True rats" are members of the genus Rattus, the most important of which to humans are the black rat, Rattus rattus, and the brown rat, Rattus norvegicus...
and may represent an endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
-derived hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
factor.
2-Arachidonyl glyceryl ether's structure can be determined by mass spectrometry
Mass spectrometry
Mass spectrometry is an analytical technique that measures the mass-to-charge ratio of charged particles.It is used for determining masses of particles, for determining the elemental composition of a sample or molecule, and for elucidating the chemical structures of molecules, such as peptides and...
and Rutherford backscattering spectrometry
Rutherford backscattering spectrometry
Rutherford backscattering spectrometry is an analytical technique used in materials science. Sometimes referred to as high-energy ion scattering spectrometry, RBS is used to determine the structure and composition of materials by measuring the backscattering of a beam of high energy ions...
. It was confirmed by comparison with a synthetic sample
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
of the endocannabinoid. It binds to the Cannabinoid receptor type 1
Cannabinoid receptor type 1
The cannabinoid receptor type 1, often abbreviated to CB1, is a G protein-coupled cannabinoid receptor located in the brain. It is activated by endocannabinoid neurotransmitters including anandamide and by the compound THC, found in the psychoactive drug cannabis.-Expression:The CB1 receptor is...
(Ki = 21.2 ± 0.5 nM), which causes sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
, hypothermia
Hypothermia
Hypothermia is a condition in which core temperature drops below the required temperature for normal metabolism and body functions which is defined as . Body temperature is usually maintained near a constant level of through biologic homeostasis or thermoregulation...
, intestinal immobility
Immobilized enzyme
An immobilized enzyme is an enzyme that is attached to an inert, insoluble material such as calcium alginate . This can provide increased resistance to changes in conditions such as pH or temperature...
, and mild antinociception in mice
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
. The endocannabinoid exhibits Ki values of 21.2 nM and >3 µM at the Cannabinoid receptor type 1 and the peripheral cannabinoid receptors.
The presence of 2-AGE in body tissue is disputed. Although a research group from Teikyo University
Teikyo University
is a private university headquartered in the Itabashi ward of Tokyo, Japan. It was established in 1931 as Teikyo Commercial High School by Lee. It became Teikyo University in 1966...
, Kanagawa, 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 Ki 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 TRPV1TRPV1
The transient receptor potential cation channel subfamily V member 1 ', also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene...
channel. After binding to CB2 receptors it inhibits adenylate cyclase
Adenylate cyclase
Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
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
Intraocular pressure 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 from glaucoma...
, increases the uptake of GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
in the globus pallidus
Globus pallidus
The globus pallidus also known as paleostriatum, is a sub-cortical structure of the brain. Topographically, it is part of the telencephalon, but retains close functional ties with the subthalamus - both of which are part of the extrapyramidal motor system...
of rats and is neuroprotective by binding to and activation of PPARα.