oa Editorial [Hot topic: The Medicinal Chemistry of Endocannabinoid System 25 Jan (Guest Editors: Tapio Nevalainen and Anna Minkkila)]

The endocannabinoid system is a complex signaling system consisting of central and peripheral cannabinoid receptors (CB1 and CB2), their endogenous ligands and metabolic enzymes inactivating the endocannabinoids, fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL). Due to the many versatile roles in human physiology, the proteins involved in the endocannabinoid system are potential targets for the treatment of wide range of physiological and pathological processes such as cardiovascular/respiratory disorders, pain, inflammation, energy metabolism disorders, cancer and central nervous system disorders. There is currently a great interest in selective cannabinoid ligands and endocannabinoid-hydrolyzing enzyme inhibitors without undesirable side effects in the central nervous system (CNS). The current journal issue comprises of five review articles, which deal with different aspects of medicinal chemistry of endocannabinoid system. In the first review Dr. Joong-Youn Shim discusses the recent molecular modeling studies of structural features of the central CB1 receptor: studies of the functional residues involved in ligand binding and recent knowledge of the CB1 homology models. He also outlines possible molecular mechanisms of receptor activation. The second review, by Dr. Charles Lunn, surveys the current knowledge of CB2 inverse agonists and their biological effects. The peripheral cannabinoid CB2 receptor is alluring target for drug therapy, because it is not likely to cause unwanted CNS side effects induced by central CB1 receptor. For example, the selective CB1 receptor antagonist rimonabant (Acomplia) was withdrawn from the market because of psychiatric side effects. The third review, by Dr. Irving and Dr. Nevalainen summarizes the most recent knowledge of GPR55 pharmacology. It has been suggested that this the orphan G protein coupled receptor could be a “third cannabinoid receptor”. However, the most recent data indicates that GPR55 is a receptor with cannabinoid sensitivity and its putative endogenous ligand is lysophosphatidylinositol, the chemistry of which is also covered in the review. The fourth review, by Professor Fowler et al., gives us a practical view of the potential of cannabinoid system in the treatment of cancer. This review summarizes the preclinical studies that have that have shown the potential of cannabinoids to inhibit tumor growth. The last review, by Minkkila et al. discloses the current knowledge on development of fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) inhibitors, and shortly their therapeutic potential. Inhibition of these endocannabinoid-hydrolyzing enzymes increases the tissue levels of endocannabinoids, leading in indirect activation of the cannabinoid receptors, which in turn elicits the therapeutic benefits. We thank all the contributing authors and reviewers for their excellent job of putting up together this special issue of Current Topics of Medicinal Chemistry on the medicinal chemistry of endocannabinoid system.