Anandamide structure

Pate DW (1999) Anandamide structure-activity relationships and mechanisms of action on intraocular pressure in the normotensive rabbit model. Doctoral dissertation. Kuopio University Publications, Kuopio... 

Other than that both are lipids there are no obvious structural similarities be tween anandamide and THC... 

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. 

FAAH was originally purified and cloned from rat liver microsomes and is able to catalyse the hydrolysis of anandamide and 2-AG, in addition to other long-chain fatty acid amides [25]. Studies into the structure and role of this enzyme have generated interest in the potential therapeutic applications of FAAH inhibitors [26-28]. FAAH knock-out mouse brains contained 15-fold higher levels of anandamide than their wild-type counterparts and these animals have also been shown to be more responsive to exogenously administered anandamide [29]. These animals also showed a reduced response to painful stimuli, supporting the hypothesis that FAAH inhibition may provide novel analgesics. Levels of 2-AG were not elevated in the FAAH knock-out animals, apparently due to the existence of alternative metabolic fates for this compound [30]. 

The first substrate analogue inhibitors of FAAH were reported in 1994. The anandamide analogues prepared represented three elasses of putative transition-state inhibitors a-trifluoromethyl ketones, a-ketoesters and a-ketoamides [62], In the initial sereening studies, it was found that the trifluoromethyl ketone eompounds tested were effeetive inhibitors of AEA hydrolysis. A selected set of a-keto esters also inhibited hydrolysis, while a-keto amides were ineffective. In particular, arachidonyl trifluoromethyl ketone (32), gave almost 100% inhibition of anandamide hydrolysis. A detailed investigation of the structural requirements for FAAH inhibition with a-trifluoromethyl ketones has been carried out by Roger and co-workers [63]. 

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]. 

Hampson, AJ, Hill WA, Zan Phillips M, Makriyannis A, Leung E, Eglen, RM, Bornheim LM. Anandamide hydroxylation by brain lipoxygenase metabolite structures and potencies at the cannabinoid receptor. Biophys. Biochim. Acta 1995 1259 173-179. 

Piomelli D, Beltramo M, Glasnapp S, Lin SY, Goutopoulos A, Xie XQ, Makriyannis A. Structural determinants for recognition and translocation by the anandamide transporter. Proc Natl Acad Sci USA 1999 10 5802-5807. 

Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandel-baum A, Mechoulam R and Etinger A (1992). Isolation and structure of a brain constituent that binds to the cannabinoid receptor (arachidonylethanolamide, anandamide ). Science, 258, 1946-1949. 

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. 

The anandamide precursor, phosphatidylethanol amine, is present in membranes almost always accompanied by phophatidylserine. It seemed reasonable to expect the formation of anandamide from its precursor will be paralleled by formation of N-arachidinoylserine from phosphatidyl serine. Indeed, A -arachidonoyl-L-serine (ARA-S) was found to be formed alongside anandamide (Fig. 4). This compound was isolated from bovine brain and its structure was elucidated by comparison with synthetic ARA-S. Contrary to anandamide, ARA-S binds very weakly to the known cannabinoid CBi and CB2 or vanilloid TRPVl receptors. However, it produces endothelium-dependent vasodilation of rat isolated mesenteric... 

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. 

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 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). 

Hampson, A. J., Hill, W. A. G., Zan-Phillips, M., Makriyannis, A., Leung, E., Eglen, R. M., and Bornheim, L. M. (1995). Anandamide hydroxylation by brain lipoxygenase Metabolite structures and potencies at the cannabinoid receptor. Biochim. Biophys. Acta 1259, 173—179. 

Structural determinants for recognition and translocation by the anandamide transporter. 

Fig. 19 The energy-minimized (AMI) structure of encapsulated anandamide inside doubly-expanded capsule 1.28.1...

Structurally there is little in common between A9-THC and anandamide. The cannabinoids are terpenophenols, while the anandamides are fatty acid derivatives. Yet, pharmacologically they have much in common. Both A9-THC and anandamide were shown to cause a typical tetrad of behavioural actions hypothermia, hypomotility, antinociception and catalepsy. In most behavioural tests, anandamide is somewhat less potent than d9-THC [35, 36]. Repeated injections of anandamide (i.p.) produced tolerance to a challenge with THC or anandamide. This tolerance however was less persistent than that commonly seen with THC, lasting for only one week [37],... 

Bisogno T (2008) Endogenous cannabinoids structure and metabohsm. J Neuroendociinol 20 1-9 Bisogno T, Melck D, Bobrov MY, Gretskaya NM, Bezuglov VV, De Petrocellis L, Di Marzo V (2000) N-acyl-dopamines novel synthetic CBl cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimemetic activity in vitro and in vivo. Biochem J 351 817-824... 

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

Endogenous ligands for the cannabinoid receptor have not yet been identified. Arachidonylethanolamide, a new arachidonic acid derivative named anandamide, was isolated from porcine brain. Its structure was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. It inhibits the specific binding of a labelled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands, and produces a concentration-dependent inhibition of the electrically-evoked twitch response of the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. Similar compounds were synthesized and their pharmacological properties were investigated. 

The structure of anandamide was established by mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy. Additional data wereobtained from the GC-MS and CID measurements of the trimethylsilyl (TMS) derivative of the material. The results suggest that anandamide is an ethanolamide of a tetraenic C20 fatty acid. 

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