In 1992 we reported (Science, 258, 1946-1949) the isolation from porcine brain, the structure elucidation and synthesis of anandamide (arachidonylethanolamide) - the first identified endogenous ligand for the cananabinoid receptors. Since then we have found two additional active fatty acid ethanolamides in brain. Recently we identified a different type of ligand - an ester - present in the gut - 2-arachidonyl glycerol (2-Ara-Gl) which also binds to the cannabinoid receptors. We have not detected 2-Ara-Gl in porcine brain. Apparently the endogenous cannabinoid ligands represent a whole family of related natural products in various tissues. Indeed we have preliminary evidence for the presence of additional ligands in the brain, in the spleen and in testes. The main objective of the research proposal is to obtain in pure form, elucidate the structures of these endogenous cannabinoids and make them available for further investigations through synthesis. The methodology in the isolation work will be column, thin layer (normal and reverse phase), and high-pressure liquid chromatography. The structure elucidation will make use mainly of mass spectrometry and, if enough material is isolated, of NMR techniques. The synthetic procedures will have to be decided upon when the structures of the active compounds are elucidated. This research may help understand the mode of action of Cannabis, its receptor and mediators, and may add to our knowledge of numerous systems in the body. This proposal is submitted together with several other proposals by collaborating groups.
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