Mini Reviews in Medicinal Chemistry - Volume 5, Issue 7, 2005

Cannabinoids have been predominantly considered as the substances responsible of the psychoactive properties of marijuana and other derivatives of Cannabis sativa. However, these compounds are now being also considered for their therapeutic potential, since the term “cannabinoid” includes much more compounds than those present in Cannabis sativa derivatives. Among them, there are numerous synthetic cannabinoids obtained by modifications from plant-derived cannabinoids, but also from the compounds that behave as endogenous ligands for the different cannabinoid receptor subtypes. Within the family of “cannabinoid-related compounds”, one should also include some prototypes of selective antagonists for these receptors, and also the recently developed inhibitors of the mechanism of finalization of the biological action of endocannabinoids (transporter + FAAH). All this boom of the cannabinoid pharmacology has, therefore, an explanation in the recent discovery and characterization of the endocannabinoid signaling system, which plays a modulatory role mainly in the brain but also in the periphery. The objective of the present article will be to review, from pharmacological and biochemical points of view, the more recent advances in the study of the endocannabinoid system and their functions in the brain, as well as their alterations in a variety of pathologies and the proposed therapeutic benefits of novel cannabinoid-related compounds that improve the pharmacokinetic and pharmacodynamic properties of classic cannabinoids.

Since the discovery that cannabinoids exert biological actions through binding to specific receptors, signal mechanisms triggered by these receptors have been focus of extensive study. This review summarizes the current knowledge of the signalling events produced by cannabinoids from membrane receptors to downstream regulators. Two types of cannabinoid receptors have been identified to date: CB1 and CB2 both belonging to the heptahelichoidal receptor family but with different tissue distribution and signalling mechanisms. Coupling to inhibitory guanine nucleotide-binding protein and thus inhibition of adenylyl cyclase has been observed in both receptors but other signal transduction pathways that are regulated or not by these G proteins are differently activated upon ligand-receptor binding including ion channels, sphingomyelin hydrolysis, ceramide generation, phospholipases activation and downstream targets as MAP kinase cascade, PI3K, FAK or NOS regulation. Cannabinoids may also act independently of CB1or CB2 receptors. The existence of new unidentified putative cannabinoid receptors has been claimed by many investigators. Endocannabinoids activate vanilloid TRPV1 receptors that may mediate some of the cannabinoid effects. Other actions of cannabinoids can occur through non-receptor-mediated mechanisms.

The CB1 receptor is expressed in the central nervous system and numerous other tissues including heart, lung and uterus and has been recognized as an important therapeutic target for pain, appetite modulation, glaucoma, multiple sclerosis and other indications. An interesting feature of this GPCR is its ability to be activated by a number of structurally different classes of compounds, thus, raising the possibility of multiple activated forms of the receptor. Understanding of the structure-activity relationships of cannabinergic ligands has paved the road for the development of novel ligands exhibiting receptor subtype selectivity and efficacy. This review highlights the important CB1 cannabinergic ligands developed to date.

The CB1 receptor is found principally in the central nervous system and is responsible for the overt physiological effects of cannabinoids. In contrast, the CB2 receptor is expressed primarily in the immune system and is responsible for few, if any, obvious behavioral effects. Although many cannabinoid receptor ligands show little, or at best modest, selectivity for either receptor, a number of synthetic compounds are known which have significant selectivity for the CB2 receptor. These include cannabimimetic indoles, such as 1-propyl-2-methyl-3-(1-naphthoyl)indole (JWH-015) and 1-(2,3-dichlorobenzoyl)-2-methyl-3-(2-[1-morpholino] ethyl)-5-methoxyindole (L768242), both of which have good affinity for the CB2 receptor, but weak affinity for the CB1 receptor. Efforts have been made to develop structure-activity relationships (SAR) at CB2 for cannabimimetic indoles, but with limited success. Several derivatives of traditional dibenzopyran based cannabinoids have also been found to have significant selectivity for the CB2 receptor. These include 1- methoxyΔ8-THC derivatives, 1-methoxyΔ8-THC-DMH (L759633), 1-methoxyΔ9(11)-THC-DMH (L759656), and 1-methoxy-3-(1',1'-dimethylhexyl)Δ8-THC (JWH-229), plus a number of 1-deoxyΔ8-THC analogues. In particular, 1-deoxy-3-(1',1'-dimethylbutyl)Δ8-THC (JWH-133) shows two hundred-fold selectivity for the CB2 receptor. Very recently several compounds belonging to other structural groups have also shown selectivity for the CB2 receptor. This review will describe the current status of the results of these studies and discuss the SAR for these classes of ligands.

In absence of X ray crystal structures of G-protein coupled receptors (GPCRs)-ligand complexes, computer-aided molecular modeling together with site-directed mutagenesis studies become of great importance in order to provide in-silico predictions that facilitate the development of new ligands. In this context, the present review addresses the application of these strategies to the CB1 and CB2 cannabinoid receptors. The combination of these complementary approaches represents a tool of considerable value which has allowed to understand the specific ligand-receptor interactions.

Novel pharmacological tools and the generation of null-mutants enabled the elucidation of the role of endocannabinoids in cognition and emotionality of rats and mice. Endocannabinoids seem to limit memory retention, to facilitate memory extinction and to ensure adequate coping with stressful situations. A selective potentiation of these actions may lead to novel pharmacotherapies for human anxiety disorders.

There is a growing amount of evidence suggesting that cannabinoids may be neuroprotective in CNS inflammatory conditions. Advances in the understanding of the physiology and pharmacology of the cannabinoid system have increased the interest of cannabinoids as potential therapeutic targets. Cannabinoid receptors and their endogenous ligands, the endocannabinoids, have been detected in cells of the immune system, as well as in brain glial cells. In the present review it is summarized the effects of cannabinoids on immune reactivity and on the regulation of neuroinflammatory processes associated with brain disorders with special attention to chronic inflammatory demyelinating diseases such as multiple sclerosis.

From library shaping to ADME-Tox prediction via virtual screening, computational chemistry is an integral component of Lead Generation. It provides a series of tools that help focusing on compounds with a balanced pharmacodynamic and ADME-Tox profile together with a high potential to optimize potency and selectivity.

Genetic alterations are responsible for all cancers. These mutations produce, in turn, alterations in key proteins of certain signaling pathways. Amongst the best known and studied alterations related to malignant transformations are those which occur in Ras protein and p53. In most cases mutations in Ras and p53 lead to the appearance of practically most malignant transformations. Mutated Ras genes exist in approximately 20 to 30% of all human cancers. Ras proteins are switches that regulate diverse functions such as cell proliferation, differentiation and apoptosis. Normal p53 expression, also known as the “genome guardian”, is a key molecule for suppressing cell proliferation. The great importance of these proteins rests on their intimacy with the events leading to cell proliferation or death. The comprehension of the extent of transformation on Ras and p53, and of the diverse biochemical pathways of intracellular signaling, activated by them, is of extreme importance for the understanding of malignant transformation, as well as its control, through the creation, for example, of new drugs which contribute to the elimination of these cells. To clarify the consequences originated by transformed Ras, p53 and their biochemical interlinks in the different intracellular pathways, besides the possible intervening points and pharmacological controls presently used in combating cancer, are the aims of this review.