Anandamide endocannabinoids 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. 

The development of SAR for endocannabinoid-derived structures has primarily focused on the anandamide skeleton (1) with a large number of publications addressing the requirements for activity and stability of this scaffold. More recently, some SAR has begun to emerge for the other end-ocannabinoids, in particular 2-AG (2). The following discussion will focus on highlighting some of the main features that contribute to affinity and/or stability each endocannabinoid will be treated separately. A number of detailed reviews on this subject have been published [142-146]. 

THE BRAIN S OWN MARIJUANA-LIKE NEUROTRANSMITTER The very high potency and structure of the cannabinoids contained within the marijuana plant enable them to cross the blood—brain barrier and bind to a receptor for the brain s very own endogenous cannabinoid neurotransmitter system. If this were not true, then the marijuana plant would be popular only for its use in making rope, paper, and cloth. The two currently identified neurotransmitters compounds (and there are probably more) in this system are anandamide, from the Sanskrit word amnia () meaning bliss, and 2-AG (2-arachidonoyl-glycerol). Unlike the other neurotransmitters that I ve discussed, these two endocannabinoids are not stored in synaptic vesicles. 

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

Members of the eicosanoid group of cannabinoid receptor agonists have markedly different structures both from the aminoalkylindoles and from classical and nonclassical cannabinoids. Important members of this group are the endocannabinoids, arachidonoylethanolamide (anandamide), 0-arachidonoylethan-olamine (virodhamine), 2-arachidonoyl glycerol and 2-arachidonyl glyceryl... 

Fig. 1. Representative structures ofthe different cannabinoid receptor ligand classes the plant cannabinoid, A -tetrahydrocannabinol the endocannabinoid, arachidonoyl ethanolamide (anandamide) the synthetic pyrazole inverse agonist AM281 and the potent aminoalkylindole agonist AM2233. Both AM281 and AM2233 contain an iodine atom that has been labeled with radioiodine for in vitro and in vivo binding experiments...

Lynch DL and Reggio PH (2005) Molecular dynamics simulations of the endocannabinoid N-arachidonoyl-ethanolamine (anandamide) in a phospholipid bilayer probing structure and dynamics. J Med Chem 48 4824-4833. 

FIGURE 8.1 The principal endogenous cannabinoids. Anandamide and 2-arachidonyl glycerol (2-AG) are the most well-studied endocannabinoids however, conjugates with other fatty acids such as palmitic and eicosapenteneoic acid are well known. Novel structures such as virodhamine and noladin ether have also been reported. Arachidonic acid derivatives with other molecules such as dopamine (NADA) and glycine (NAGly) are also known. 

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 ... 

Figure 1. Structures of A -tetrahydrocannabinol (A -THC) and endocannabinoids. K values of anandamide, 2-arachidonoylglycerol (2-AG) and 2-arachidonylglyceryl ether for CB and CB receptors are presented.

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). 

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