Ethanolamides, brain

Hanus L, Gopher A, Almog S, Mechoulam R. Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor. J Med... 

Our research group expected that additional polyunsaturated fatty acid ethanolamides may be present in the brain. We also identified in porcine brain another two putative endocannabinoids, namely homo-y-linoleoylethanolamide (K = 53.4 5-5 nM) and 7,10,13,16-docosatetraenoylethanolamide (K = 34.4 3.2 nM). The isolation of these two compounds as constituents of porcine brain that bind to the cannabinoid receptor demonstrated that anandamide is not the sole representative of this class of potential mediators. 

Analogous to the discovery of the endogenous opiates and opiate receptors, the discovery of cannabinoid receptors in 1988 suggested the presence of endogenous cannabimimetic compounds. In 1992 anandamine—the ethanolamide of arachidonic acid was purified from porcine brain and shown to behave... 

Recently, the ethanolamide of arachidonic acid (anandamide ananda is the Sanskrit word for bliss) (Figure 3.53) has been isolated from animal brain tissue, and has been shown... 

As an example of the application of metabolomics, we will refer to the substrates of the enzyme fatty acyl amide hydrolase (FAAH) that regulates several brain lipids that have interesting pharmacological properties including effects on the control of pain. It is well known that some fatty acyl amides of ethanolamine are substrates of FAAH, such as the ethanolamide of arachidonic acid (anandamide), which is an endogenous ligand of cannabinoid receptors. 

Figure 5.3 Bioactive fatty acid ethanolamides in porcine brain.

Figure 5.3). The most abundant of these ligands is arachidonoylethanola-mide (anandamide, 7) [33, 34], Two additional anandamides isolated from porcine brain are docosatetraenoylethanolamide and dihomo-y-linolenoyl-ethanolamide [34] (see Figure 5.3).

The discovery of cannabinoid receptors naturally stimulated a search for an endogenous ligand with which the receptors naturally interact. Such a substance was isolated from the pig brain. It was found to be chemically different from plant cannabinoids it is a derivative of the fatty acid arachidonic acid (arachidonyl ethanolamide) related to the prostaglandins. This endogenous substance was named anandamide after the Sanskrit word for bliss, ananda. It has a high affinity for CBi receptors and has most of the actions of THC. 

Arachidonic acid ethanolamide (anandamide) and similar compounds are constituents of the brain. Anandamide and certain of the compounds similar with same, bind to the cannabinoid receptor. The binding of the ananamide to the cannabinoid receptor is similar to the binding of A9-tetrahydrocannabinol. There exist in the body many mediators, which are derivatives of arachidonic acid, such as prostaglandins and leukotrienes, which are present as large families of related compounds. Certain of these do not bind to the cannabinoid receptor, and it was one of the aims of the present invention to provide and identify compounds which have pharmacological properties similar to the properties of anandamide. 

Arachidonyl ethanolamide (anandamide) is a naturally-occurring brain constituent that acts as a CBl and CB2 agonist and exhibits pharmacological activity in mice comparable to cannahinoids (Fride and Mechoulam (1993), Crawley et al. (1993) and Smith et al. (1994)). Anandamide is cleaved in vivo by anandamide amidase. Thus, inhibitors of anandamide amidase have the effect of indirectly stimulating the CBl and CB2 receptors by increasing in vivo levels of anandamide. In addition to acting at the CBl and CB2 receptors, cannahinoids also affect cellular membranes, thereby producing undesirable side effects... 

Blount, B.K. Robinson, R. Derivatives of 1-Methyltropane 1933 Boger, L. R. Inhibitors of Fatty Acid Amide Hydrolase 2002 US 6,462,054 Boring D.L, Berglund, B.A, Howlett A.C. Cerebrodiene, Arachidonyl-ethanolamide, and Hybrid Structures Potential for Interaction with Brain Cannabinoid Receptors Prostaglandins Leukot Essent Fatty Acids. (1996) 55(3) 207-10. 

Tetrahydrocannabinol (THC), the psychoactive marijuana plant- derived cannabinoid, and numerous synthetic derivatives have been shown to bind to a specific brain receptor, cannabinoid receptor 1 (CBl) (Howlett et al. 1990 Matsuda et al. 1990 Herkenham et al. 1990 Mailleux and Vanderhagen 1992). Arachidonoyl ethanolamide (anandamide), homo—linolenyl ethanolamide, and docosatetraenyl ethanolamide are naturally occurring brain constituents that bind to CBl and as a class are called the anandamides (Mechoulam et al. 

Burstein and Hunter (1995) observed that THC stimulated the biosynthesis of anandamide in neuroblastoma cells employing either ethanolamine or arachidonic acid as the label. Anandamide bios5mthesis has also been shown to occur in primary cultures of rat brain neurons labelled with [H]-ethanolamine when stimulated with ionomycin, a Ca ionophore (Di Marzo et al. 1994). These authors proposed an alternate model for the biosynthesis of anandamide in which N-arachidonoyl phosphatidyl ethanolamine is cleaved by a phospholipase D activity to yield phosphatidic acid and ararchidonoylethanolamide. This model is based upon extensive studies undertaken by Schmid and collaborators (1990), who have shown that fatty acid ethanolamide formation results from the N-acylation of phosphatidyl ethanolamine by a transacylase to form N-acyl phosphatidylethanolamine. Possibly resulting from postmortem changes, this compound is subsequently hydrolyzed to the fatty acid ethanolamide and the corresponding phosphatide by a phosphodiesterase, phospholipase D. 

Interestingly, the enzymatic activities found for anandamide amidase may be related to those reported in the literature for the hydrolysis of other fatty acid amides. Bachur and Udenfriend (1966) and Schmid and colleagues (1990) described a rat liver microsomal enzyme that hydrolyzed fatty acid ethanolamides. Natarajan and colleagues (1984) described activity in a dog brain microsomal fraction that hydrolyzed... 

Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296 678-682 Yu M, Ives D, Ramesha CS (1997) Synthesis of prostaglandin E2 ethanolamide from anan-... 

Boring DL, Berglund BA, and Howlett AC (1996) Cerebrodiene, arachidonyl-ethanolamide, and hybrid structures potential for interaction with brain cannabinoid receptors. Prostaglandins Leukot Essent Fatty Acids 55 207-10. 

PGEj ethanolamide does not bind to CB, receptors (in rat brain membranes), although it has a low affinity for CBj receptors (in human tonsilar membranes) (Berglund et al., 1999). The compound does, however, activate G-proteins in a CB -receptor-independent manner and stimulates cyclic AMP... 

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