Anandamide chemical structure

Endocannabinoids. Figure 1 Chemical structures of the two most studied endocannabinoids, anandamide and 2-arachidonoylglycerol, of Cannabis sativa psychoactive principle, A9-tetrahydrocannabinol, and of the CB-i receptor antagonist/inverse agonist, rimonabant. 

Anandamide was isolated from water-insoluble fractions of the porcine brain. It binds to CB1 with rather moderate affinity (Ki 61 nM) and a low affinity for the CB2 receptor (Ki 1930 nM). The name anandamide is based on its chemical nature (an amide) and the Sanskrit word ananda meaning bliss. The chemical structure of anandamide can be divided into two major molecular fragments a polar ethanolamido head group and a hydrophobic arachidonyl chain. The polar head group comprises a secondary amide functionality with an N-hydroxyalkyl substituent while the lipophilic fragment is a non-conjugated c/ s tetraolefinic chain and an n-pentyl chain reminiscent of the lipophilic side chain found in the classical cannabinoids. A number of anandamide analogs have been synthesized and demonstrated to have considerable selectivity for the CB1 receptor in comparison to the CB2 receptor. 

Figure 19.1. Chemical structure of main active ingredient of Cannabis sativa, A9-tetrahydrocannabinol (THC) and the naturally occurring ligand for cannabinoid receptors anandamide (arachidonyl ethanolamide).

Highly sensitive targeted lipidomic approaches are rapidly leading to the identification of new analogs of anandamide (Tan et al., 2006). The two major families of lipids that share common chemical structure with anandamide are FAEs and fatty acid amides. Although many of these lipids show no activity at CB receptors, they are known to bind and activate other receptors, such as transient receptor potential vanilloid type-1 (TRPV-1) and the nuclear receptor peroxisome proliferator-activated (PPAR-a). 

Figure 2 Endocannabinoid chemical structures (a) anandamide and (b) 2-arachidonoylglycerol. Chemical formulas and molecular weights (g/mol) are given.

The first endocannabinoid, anandamide, is an ara-chidonoyl ethanolamine, derived from fatty acids within the body. Its pharmacology is quite similar to THC although its chemical structure is different. Anandamide binds primarily to the central CB ... 

FIGURE 5.10 Chemical structure of anandamide. Three models of anandamide (arachidonoyl ethanolamide, AEA) are shown. In the first one (on the top) the region inherited from arachidonic acid (C20 4(o6) is framed. Note the four-double bonds in the cis (Z) configuration (see Chapter 1 for a description of unsaturated fatty acids). The ethanolamine part is shaded in rose. The two other models show an energy-minimized structure of anandamide in tube and sphere rendition. The arrows indicate the correspondence of chemical groups between the models. 

Fig. 6. /. The chemical structure of anandamide(N-arachidonoylethanolaminel an endogenous cannabinoid substance identified in mammalian brain tissue.

The interest in Mechoulam s study extended very rapidly from the field of Cannabis pharmacology to that of arachidonic acid biochemistry. In fact, it had not escaped the attention of many readers of the Science report that the chemical structure of the endogenous cannabinoid isolated by the Jerusalem s group—called anandamide after ananda, the Sanskrit word for bliss —was that of a unique arachidonic acid derivative, N-arachidonoylethanol-amine. This structure, depicted in Figure 6.1, clearly showed that anandamide was not produced through any of the then known metabolic transformations of free arachidonate. 

Small changes in the chemical structure of anandamide are important for the catalytic activity of anandamide amidohydrolase (Fig. 6.12). Structural modifications that result in reduced hydrolysis include (1) elongating the fatty acyl chain above 20 carbon atoms (2) replacing cis double bonds with trans double bonds (3) decreasing the number of double bounds to one, or eliminating them. ... 

We named the active constituent anandamide — based on the Sanskrit word ananda meaning delight, bliss, and on its chemical nature. A juxtaposition of the various analytical data led us to conclude that the structure of anandamide is that of arachidonoylethanolamide. This conclusion was confirmed by synthesis. 

Oleamide, a lipid originally named cerebrodiene, was first iso lated from partially sleep-deprived cats (Lerner et al 1994). The molecule, with the chemical formula C18H35NO, is a long-chain base structurally related to sphingosine and sphinganine (Lerner et al 1994). Oleamide, or cerebrodiene, is chemically characterized as cis-9,10-octadecenoamide (Cravatt et al 1995). Oleamide is degraded by the brain enzyme fatty acid amide hydrolase (FAAH), which also degrades anandamide (Cravatt et al. Nature 1996). 

A third type of endocannabinoid is noladin ether (2-arachidonylglyceryl ether) (Figure 1), which was recently isolated from porcine brain (Hanus et al, 2001). In contrast to the chemical nature of anandamide (an amide) and 2-AG (an ester), this endocannabinoid is an ether. Apart from the structural differences, noladin ether also differs from anandamide and 2-AG in its cannabinoid receptor binding. It binds to the CBj cannabinoid receptor (K = 21.2 0.5 nM) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. However, in contrast to anandamide and 2-AG it binds very weakly to the CB receptor (K. > 3000 nM). 

The chemical synthesis of anandamide confirmed this structural identification, and allowed Mechoulam, Devane and their colleagues to determine its pharmacological properties. In vitro and in vivo tests showed a great similarity of effects between anandamide and cannabinoid drugs. Anandamide reduced the electrogenic contraction of mouse vas deferens and, most importantly, closely mimicked the behavioral responses induced by... 

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