Anandamide (ANA), also referred to as N-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-Acylethanolamine (NAE). Anandamide takes its name from the Sanskrit word ananda, meaning "joy, bliss, delight," plus amide. Anandamide, the first discovered endocannabinoid, engages with the body's endocannabinoid system by binding to the same cannabinoid receptors that THC found in cannabis acts on. Anandamide can be found within tissues in a wide range of animals. It has also been found in plants, such as the cacao tree.
Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important regulatory hormone in lipolysis is insulin; lipolysis can only occur when insulin action falls to low levels, as occurs during fasting. Other hormones that affect lipolysis include leptin, glucagon, epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol.
Monoglycerides are a class of glycerides which are composed of a molecule of glycerol linked to a fatty acid via an ester bond. As glycerol contains both primary and secondary alcohol groups two different types of monoglycerides may be formed; 1-monoacylglycerols where the fatty acid is attached to a primary alcohol, or a 2-monoacylglycerols where the fatty acid is attached to the secondary alcohol.
EX-597, is a fatty acid amide hydrolase inhibitor which is under development for the treatment of social anxiety disorder and post-traumatic stress disorder (PTSD).
The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system and peripheral nervous system. The endocannabinoid system remains under preliminary research, but may be involved in regulating physiological and cognitive processes, including fertility, pregnancy, pre- and postnatal development, various activity of immune system, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.
Diacylglycerol lipase, also known as DAG lipase, DAGL, or DGL, is an enzyme that catalyzes the hydrolysis of diacylglycerol, releasing a free fatty acid and monoacylglycerol:
diacylglycerol + H2O ⇌ monoacylglycerol + free fatty acid
Fatty-acid amide hydrolase 1 (FAAH) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide (AEA), an N-acylethanolamine (NAE) in 1993. In humans, it is encoded by the gene FAAH.
2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been found in maternal bovine and human milk. The chemical was first described in 1994–1995, although it had been discovered some time before that. The activities of phospholipase C (PLC) and diacylglycerol lipase (DAGL) mediate its formation. 2-AG is synthesized from arachidonic acid-containing diacylglycerol (DAG).
Hormone-sensitive lipase (EC 3.1.1.79, HSL), also previously known as cholesteryl ester hydrolase (CEH), sometimes referred to as triacylglycerol lipase, is an enzyme that, in humans, is encoded by the LIPE gene, and catalyzes the following reaction:
Serine hydrolases are one of the largest known enzyme classes comprising approximately ~200 enzymes or 1% of the genes in the human proteome. A defining characteristic of these enzymes is the presence of a particular serine at the active site, which is used for the hydrolysis of substrates. The hydrolysis of the ester or peptide bond proceeds in two steps. First, the acyl part of the substrate is transferred to the serine, making a new ester or amide bond and releasing the other part of the substrate is released. Later, in a slower step, the bond between the serine and the acyl group is hydrolyzed by water or hydroxide ion, regenerating free enzyme. Unlike other, non-catalytic, serines, the reactive serine of these hydrolases is typically activated by a proton relay involving a catalytic triad consisting of the serine, an acidic residue and a basic residue, although variations on this mechanism exist.
Methoxy arachidonyl fluorophosphonate, commonly referred as MAFP, is an irreversible active site-directed enzyme inhibitor that inhibits nearly all serine hydrolases and serine proteases. It inhibits phospholipase A2 and fatty acid amide hydrolase with special potency, displaying IC50 values in the low-nanomolar range. In addition, it binds to the CB1 receptor in rat brain membrane preparations (IC50 = 20 nM), but does not appear to agonize or antagonize the receptor, though some related derivatives do show cannabinoid-like properties.
JZL184 is an irreversible inhibitor for monoacylglycerol lipase (MAGL), the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol (2-AG). It displays high selectivity for MAGL over other brain serine hydrolases, including the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH), thereby making it a useful tool for studying the effects of endogenous 2-AG signaling, in vivo. Administration of JZL184 to mice was reported to cause dramatic elevation of brain 2-AG leading to several cannabinoid-related behavioral effects.
In biochemistry, lipase refers to a class of enzymes that catalyzes the hydrolysis of fats. Some lipases display broad substrate scope including esters of cholesterol, phospholipids, and of lipid-soluble vitamins and sphingomyelinases; however, these are usually treated separately from "conventional" lipases. Unlike esterases, which function in water, lipases "are activated only when adsorbed to an oil–water interface". Lipases perform essential roles in digestion, transport and processing of dietary lipids in most, if not all, organisms.
URB602 is a compound that has been found to inhibit hydrolysis of monoacyl glycerol compounds, such as 2-arachidonoylglycerol (2-AG) and 2-oleoylglycerol (2-OG). It was first described in 2003. A study performed in 2005 found that the compound had specificity for metabolizing 2-AG over anandamide in rat brain presumably by inhibiting the enzyme monoacylglycerol lipase (MAGL), which is the primary metabolic enzyme of 2-AG. However, subsequent studies have shown that URB602 lacks specificity for MAGL inhibition in vitro.
2-Oleoylglycerol (2OG) is a monoacylglycerol that is found in biologic tissues. Its synthesis is derived from diacylglycerol precursors. It is metabolized to oleic acid and glycerol primarily by the enzyme monoacylglycerol lipase (MAGL). In 2011, 2OG was found to be an endogenous ligand to GPR119. 2OG has been shown to increase glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels following administration to the small intestine. 2OG has also been discovered to potentiate G protein and not β-arrestin signaling via allosteric binding of the 5-HT2A receptor.
JZL195 is a potent inhibitor of both fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the primary enzymes responsible for degrading the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively.
IDFP is an organophosphorus compound related to the nerve agent sarin.
alpha/beta-Hydrolase domain containing 6 (ABHD6), also known as monoacylglycerol lipase ABHD6 or 2-arachidonoylglycerol hydrolase is an enzyme that in humans is encoded by the ABHD6 gene.
An endocannabinoid enhancer (eCBE) is a type of cannabinoidergic drug that enhances the activity of the endocannabinoid system by increasing extracellular concentrations of endocannabinoids. Examples of different types of eCBEs include fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, and endocannabinoid transporter (eCBT) inhibitors. An example of an actual eCBE is AM404, the active metabolite of the analgesic paracetamol and a dual FAAH inhibitor and eCBRI.
alpha/beta-Hydrolase domain containing 12 (ABHD12) is a serine hydrolase encoded by the ABHD12 gene that participates in the breakdown of the endocannabinoid neurotransmitter 2-arachidonylglycerol (2-AG) in the central nervous system. It is responsible for about 9% of brain 2-AG hydrolysis. Together, ABHD12 along with two other enzymes, monoacylglycerol lipase (MAGL) and ABHD6, control 99% of 2-AG hydrolysis in the brain. ABHD12 also serves as a lysophospholipase and metabolizes lysophosphatidylserine (LPS).
