Anandamide endocannabinoids ligands

Tian X, Guo J, Yao F, Yang DR and Makriyannis A (2005) The conformation, location, and dynamic properties of the endocannabinoid ligand anandamide in a membrane bilayer. J Biol Chem. In press. 

All the foregoing pharmacological effects of anandamide, in conjunction with the well-documented existence of specific systems for its biosynthesis, catabolism, and cellular reuptake to be discussed shortly, suggest that anandamide is indeed the endogenous cannabinoid ligand. The other two less studied A -acylethanolamide endocannabinoids and also 2-AG may serve similar functions. The differential roles of each of these four endocannabinoids are still unclear. 

Anandamide One of the endogenous ligands, or endocannabinoids, which is active at cannabinoid receptors. 

Endocannabinoids are endogenous ligands for the CB1 receptor. The best established are anandamide (N-arachidonoylethanolamine) and 2-AG (2-arachidonoyl-glycerol). Others may also exist. Pathways involved in the formation and inactivation of anandamide and 2-AG are shown in Figure 56-6. Some steps in their formation are Ca2+-dependent. This explains the ability of neuronal depolarization, which increases postsynaptic intracellular Ca2+ levels, to stimulate endocannabinoid formation and release. Some neurotransmitter receptors (e.g. the D2 dopamine receptor) also stimulate endocannabinoid formation, probably by modulating postsynaptic Ca2+ levels or signaling pathways (e.g. PLC) that regulate endocannabinoid formation. 

Another interesting member of the TRP channel family that has been characterised recently is ANKTMl, which is activated byA -tetrahydrocannabinol as well as being implicated in the detection of noxious cold (Jordt et al. 2004). However, the physiological relevance of the effect of A -tetrahydrocannabinol on ANKTMl is unclear because the endocannabinoids anandamide and 2-AG do not activate this TRP channel (Jordt et al. 2004). Nevertheless, it is possible that other as-yet-unidentified endocannabinoids act as endogenous ligands for ANKTMl. 

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...

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