Discovery and characterization of endogenous cannabinoids

The characterization of cannabinoid receptors and signal transduction mecha nisms provided the impetus for the searching for endogenous ligands for thi s system. The result was a family of fatty acid derivatives that interact w ith cannabinoid receptors to varying degrees. The two ligands that have rec eived the most attention are anandamide (AN) and 2-arachidonoly-glycerol (A ra-Gl). They are both present in central as well as peripheral tissues. Mec hanisms for the synthesis and metabolism of AN have been described. Present ly, the physiological stimuli for production and release of AN are unknown. As a result, elucidation of its physiological role remains elusive. Howeve r, it seems reasonable to conclude that both AN and 2-Ara-Gl interact with cannabinoid receptors in both peripheral and central tissue to produce a wi de range of effects. Administration of these ligands to laboratory animals produce effects that are quite similar to those elicited by Delta(9)-tetrah ydrocannabinol (THC), the psychoactive constituent in marijuana. Neverthele ss, there are some pharmacological differences between the plant-derived TH C and the endogenous cannabinoids that could be due to either pharmadynamic or pharmacokinetics dissimilarities. Extensive structure-activity relation ship studies have provided some vital insights into the actions of the endo genous ligands. First and foremost, systematic structural alterations in AN have additional support that it is acting at the cannabinoid receptors in a fashion similar to that of THC. Development of metabolically stable analo gs of AN, as well as those with greater receptor affinity, have helped subs tantiate AN and THC similarities. Nevertheless, pharmacological differences remain between the endogenous and exogenous ligands. Whether these differe nces are due to the nature of their interaction with the cannabinoid recept ors, activation of unique signaling pathways, interactions with non-cannabi noid receptors, or pharmacokinetic considerations remain to be resolved.