Anandamide derivatives

Fatty acids occur naturally m forms other than as glyceryl triesters and we 11 see numerous examples as we go through the chapter One recently discovered fatty acid derivative is anandamide... 

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]. 

In addition to anandamide, several other endogenous polyunsaturated fatty acid derivatives were also found to act as cannabimimetics. They are all now collectively referred to as endocannabinoids. Soon after the discovery of anandamide, two more fatty acid ethanolamides were isolated and found to bind to CB1 preparations with affinities similar to that of anandamide (anandamide CB1 binding affinity K = 39.2 nM, according to Hanus et al., 1993). These were the homo-y-linolenylethanol-amide (CB1 K[ = 53.4 nM) and 7,10,13,16-docosatetraenylethanolamide (CB1 K[ = 34.4 nM) (Fig. 2). All three V-acylethanolamide endocannabinoids were found to be CB1 agonists in the MVD test (Pertwee, 1994). 

Di Marzo V, Bisogno T, De Petrocellis L, Melck D, Martin BR. Canna-bimimetic fatty acid derivatives anandamide family and other endocan-nabinoids. Curr Med Chem 1999b 6 721-744. 

Edgemond WS, Hlillard CJ, Falck JR, Kearn CS, Cambell WB. Fluman platelets and polymorphonuclear leukocytes synthesize oxygenated derivatives of arachidonylethanolamide (anandamide) their affinities for canna-binoid receptors and pathways of inactivation. Mol Pharmacol 1998 54 180-188. 

Anandamide can be transported inside neural cells (neurons and glia) by a carrier-mediated facilitate diffusion mechanism (Beltramo et al., 1997) and transformed through two main pathways (1) hydrolysis to arachidonic acid and ethanolamine, and (2) oxidation to various oxygenated derivatives. 

As in the case of anandamide, 2-AG is derived from the hydrolysis of complex membrane lipids. The direct precursors of 2-AG can either be 1-acyl, 2-arachidonoyl-diacylglycerols (DAGs) or 2-arachidonoyl-lysoglycerophospholi-pids (e.g., lysophosphatidic acid, LPA). 

Best studied, among these ligands, are the lipid derivatives anandamide (AEA) (Devane etal., 1992) and 2-arachidonoylglycerol (2-AG) (Mechoulam et al., 1995 Sugiura et al., 1995), which differ from classical and peptide neurotransmitters in... 

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],... 

Alkylation or dialkylation of the a-carbon adjacent to the carbonyl group retains the level of binding in the case of anandamide. a-Monomethyl-ation or a,a-dimethylation of V-propyl derivatives potentiated binding and led to highly active compounds. 

A second antagonist, AM 630 (24b), a novel aminoalkylindole, was found to attenuate the ability of some cannabinoids to inhibit electrically-evoked twitches of the mouse isolated vas deferens [114]. AM 630 was a more potent antagonist of d9-THC than of anandamide (Kd of 14.0 and 278.8 nM, respectively). It was suggested that the receptors for which AM 630 has the highest activity may not be CB, cannabinoid receptors. This is supported by the observation that AM 630 is actually a cannabinoid agonist in the myenteric plexus - muscle preparation [115]. Yamada et al. [116] showed that isothiocyanate derivatives of pravadoline can serve as potential electrophilic affinity ligands for CB],... 

After the demonstration of THC binding sites in the CNS (26), a search for an endogenous ligand produced the long-chain ethanol-amine derivative (17) of arachidonic acid, known as anandamide (27). Subsequently, the glycerol ester of arachidonic acid (18), known as 2-AG, was shown to be a more abundant endogenous ligand in the brain than anandamide (28). Further development has tended... 

---