Current Topics in Medicinal Chemistry - Volume 10, Issue 8, 2010

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 For example, the selective CB1 receptor antagonist rimonabant (Acomplia) was withdrawn from the market because of psychiatric side effects.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.

The cannabinoid CB2 receptor continues to be an intriguing target for the potential therapeutic benefit of cannabinoids. Because this receptor is significantly found outside the brain, compounds specific for the CB2 receptor may be free of the side effects that have plagued cannabinoid CB1 receptor-based therapeutics. In this review, we will discuss a class of compounds which modulate the constitutive activity of the cannabinoid CB2 receptor, the inverse agonists. We will discuss recent chemical advances that provide new compounds to investigate the biology based on this pharmacology. We will then discuss new biology associated with the cannabinoid CB2 receptor for hints of how these compounds can best be utilized in vivo.

The brain cannabinoid (CB1) receptor that mediates numerous physiological processes in response to marijuana and other psychoactive compounds is a G protein-coupled receptor (GPCR) and shares common structural features with many rhodopsin class GPCRs. For the rational development of therapeutic agents targeting the CB1 receptor, understanding the ligand-specific CB1 receptor interactions responsible for unique G protein signals is crucial. For more than a decade, a combination of mutagenesis and computational modeling approaches has been successfully employed to study the ligand-specific CB1 receptor interactions. In this review, after a brief discussion about recent advances in understanding of some structural and functional features of GPCRs commonly applicable to the CB1 receptor, the CB1 receptor functional residues reported from mutational studies are divided into three different types, ligand binding (B), receptor stabilization (S) and receptor activation (A) residues, to delineate the nature of the binding pockets of anandamide, CP55940, WIN55212-2 and SR141716A and to describe the molecular events of the ligand-specific CB1 receptor activation from ligand binding to G protein signaling. Taken these CB1 receptor functional residues, some of which are unique to the CB1 receptor, together with the biophysical knowledge accumulated for the GPCR active state, it is possible to propose the early stages of the CB1 receptor activation process that not only provide some insights into understanding molecular mechanisms of receptor activation but also are applicable for identifying new therapeutic agents by applying the validated structure-based approaches, such as virtual high throughput screening (HTS) and fragment-based approach (FBA).

Increasing experimental studies indicate the existence of novel molecular targets for cannabinoid ligands and recently it has been suggested that the orphan G-protein coupled receptor, GPR55 can be activated by a range of endogenous, plant and synthetic cannabinoids. However, to date, the most potent ligand identified for GPR55 is the endogenous phospholipid, lysophosphatidylinositol (LPI). GPR55 is thought to link predominantly to G-protein α13, where it promotes Rho-dependent signalling. Additional events downstream of GPR55 include activation of ERK-MAP kinase and Ca2+ release from stores, as well as the induction of a number of transcription factors. Although GPR55 has only a low sequence identity with the CB1 or CB2 cannabinoid receptors, it clearly interacts with certain cannabinoid ligands. However, the nature and scope of these effects are presently unclear and they may be influenced by the assay and cellular background used for their study. This article reviews the current status of GPR55 pharmacology and its putative endogenous ligand, LPI.

In recent years, considerable interest has been generated by findings that cannabinoids not only have useful palliative effects, but also can affect the viability and invasivity of a variety of different cancer cells. In the present review, the potential of targeting the cannabinoid system for the treatment of cancer is considered from a practical, rather than a mechanistic viewpoint, addressing questions such as whether human tumour cells express CB receptors; whether the potencies of action of cannabinoids in vitro match the potencies expected on the basis of receptor theory; what is known about the in vivo effects of cannabinoids and cancer, and how relevant the experiments undertaken are to the clinical situation; and finally, what approaches can be taken to minimise unwanted effects of cannabinoid treatment. It is concluded that cannabinoids (or agents modulating the endogenous cannabinoid system) are an attractive target for drug development in the cancer area, but that more in vivo studies, particularly those investigating the potential of cannabinoids as an addition to current treatment strategies, are needed.

Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) are hydrolytic enzymes which degrade the endogenous cannabinoids (endocannabinoids) N-arachidonoylethanolamine (anandamide, AEA) and 2- arachidonoylglycerol (2-AG), respectively. Endocannabinoids are an important class of lipid messenger molecules that are produced on demand in response to elevated intracellular calcium levels. They recognize and activate the cannabinoid CB1 and CB2 receptors, the molecular targets for Δ9-tetrahydrocannabinol (Δ9-THC) in marijuana evoking several beneficial therapeutic effects. However, in vivo the cannabimimetic effects of AEA and 2-AG remain weak owing to their rapid inactivation by FAAH and MGL, respectively. The inactivation of FAAH and MGL by specific enzyme inhibitors increases the levels of AEA and 2-AG, respectively, producing therapeutic effects such as pain relief and depression of anxiety. A variety of chemically diverse FAAH and MGL inhibitors have been developed and synthesized recently. Thus, this article reviews the scientific literature of various FAAH and MGL inhibitors presented during the past ten years.