Chemical structure, endocannabinoids

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. 

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

Fig. 1 Chemical structures of the putative endocannabinoids identified to date...

Fig. 1. Established and newly proposed endocannabinoids. Chemical structures ofthe five endogenous cannabinoid ligands identified so far...

Fig. 4. Chemical structures of inhibitors of endocannabinoid biosynthesis or inactivation...

FIGURE 6.1 Chemical structures of endocannabinoids and of possible templates for the development of ligands of putative novel cannabinoid receptors. 

The SAR studies of endocannabinoids have been reviewed (80-83). The chemical structure of anandamide can be divided into two major molecular fragments (67, Fig. 8) a polar ethanolamido head group and a hydrophobic arachidonoyl chain. The polar head group is comprised of a secondary amide functionality with an A-hydroxyalkyl substituent, while the hydrophobic fragment is a nonconjugated all-cw tetraolefinic chain and an n-pentyl tail reminiscent of the lipophilic side chain found in the classical caimabinoids. 

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 ... 

In recent years the rapid development of high-sensitivity analytical techniques such as mass spectrometry (MS) and liquid chromatography (LC) supported the investigation of the endocannabinoids as part of a complex lipid network. The identification of lipid components of the endocannabinoid system can be achieved in a single analytical step by state-of-the-art platforms such as tandem mass spectrometry (MS/MS), which provides the detailed structural information necessary for characterization of lipids and increases specificity in complex biological matrices. Furthermore, the implementation of ionization techniques such as electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) allow the coupling of LC to MS, and permits the separation and analysis of endocannabinoids with greater speed and accuracy. 

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). 

By definition, cannabinoids comprise a variety of distinct chemical classes which bind to the cannabinoid receptor. These include the classical cannabinoids structurally related to tetrahydrocannabinol, the non-classical cannabinoids, the aminoalkylindoles, the eicosanoids related to the endocannabinoids, 1,5-diarylpyrazoles, quinolines and atylsulphonamides and additional compounds that do not fall into these standard classes. According to their production and origin, there are three types of cannabinoids phytocannabinoids, endogenous cannabinoids, and synthetic cannabinoids. 

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