Current Topics in Medicinal Chemistry - Volume 8, Issue 3, 2008

The utilization of the hemp plant, Cannabis sativa L. has a millenia long history. The therapeutic potential of the plant was recognized early and most parts of the plant have been exploited, for example, in medicine or in various religious rituals. The major psychoactive substance of cannabis, Δ9-tetrahydrocannabinol (THC), was isolated only in the 1960s. THC and other structurally similar compounds characterized from this plant were all named cannabinoids. Over the years, numerous cannabinoid analogues have been synthesized in the hope of developing potential drugs for therapeutic use. Unfortunately, the unwanted psychotropic effects of the cannabimimetic molecules have limited their medical application. However in the 1990s, the discovery of the endogenous cannabinoid system revolutionized the cannabinoid research field. This complex lipid signaling system in humans includes specific cannabinoid receptors (at least CB1 and CB2), their endogenous ligands (endocannabinoids) and the enzymes responsible for synthesizing or degrading the endocannabinoids (e.g. fatty acid amide hydrolase, FAAH, or monoacylglycerol lipase, MAGL), and it provides an intriguing target for the design and development of selective cannabinoid drugs. The current journal issue focuses on the chemical agents that have been discovered or developed to target the endogenous cannabinoid system. The review by Wolkart et al. introduces us to the world of phytocannabinoids. Phytocannabinoids from Cannabis sativa L. are the best known cannabinoid compounds and have contributed greatly to the discovery of the endogenous cannabinoid system and understanding its functions. However, cannabinoid-type compounds have also been found in Echinacea species and liverwort, as well as in Helichrysum umbraculigerum. The authors present the phytocannabinoids as useful templates for drug design and especially discuss current studies of their effects on the immune system. Unlike the central CB1 receptors, CB2 receptors are mainly located in the immune system. Therefore, selective CB2 receptor ligands are potential immunotherapeutic agents and they do not cause the unwanted psychotrophic effects related to the CB1 agonism of the non-selective cannabinoids. Marriott and Huffman give a comprehensive review of selective CB2 ligands developed to date. Especially the structure-activity relationships of traditional cannabinoid and indole analogues have been studied extensively. Another way of avoiding the unwanted psychotrophic effects is to block the CB1 receptors. Jagerovic et al. review the structure-activity relationships of CB1 selective antagonists/inverse agonists, which are potential therapeutic agents for the treatment of obesity and nicotine addiction. In addition to the extensively studied analogues of rimonabant (Acomplia®), there are also some other structural scaffolds that have been shown to have antagonistic/inverse agonistic effects at CB1. Fine-tuning of the levels of the endocannabinoids is yet another intelligent approach to overcome the problems associated with direct CB1 activation. Viso and co-authors present the current knowledge on MAGL, the enzyme hydrolyzing 2- arachidonoylglycerol, the endocannabinoid. They focus especially on the enzyme structure and catalytic mechanism, as well as on the therapeutic potential of MAGL inhibitors. Severine Vandevoorde compares different structural families of FAAH and MAGL inhibitors. In addition to the chemical features, modes of inhibition, potencies and FAAH/MAGL selectivities of the inhibitors, their synthetic pathways are also presented.

Advances in understanding the physiology and pharmacology of the endogenous cannabinoid system have potentiated the interest of cannabinoid receptors as potential therapeutic targets. Cannabinoids have been shown to modulate a variety of immune cell functions and have therapeutic implications on central nervous system (CNS) inflammation, chronic inflammatory conditions such as arthritis, and may be therapeutically useful in treating autoimmune conditions such as multiple sclerosis. Many of these drug effects occur through cannabinoid receptor signalling mechanisms and the modulation of cytokines and other gene products. Further, endocannabinoids have been found to have many physiological and patho-physiological functions, including mood alteration and analgesia, control of energy balance, gut motility, motor and co-ordination activities, as well as alleviation of neurological, psychiatric and eating disorders. Plants offer a wide range of chemical diversity and have been a growing domain in the search for effective cannabinoid ligands. Cannabis sativa L. with the known plant cannabinoid, Δ9-tetrahydrocannabinol (THC) and Echinacea species with the cannabinoid (CB) receptor-binding lipophilic alkamides are the best known herbal cannabimimetics. This review focuses on the state of the art in CB ligands from plants, as well their possible therapeutic and immunomodulatory effects.

Two subtypes of the mammalian cannabinoid receptor have been identified and successfully cloned since 1990. The CB1 receptor is primarily located in the central nervous system and the CB2 receptor is almost exclusively expressed in cells of the immune system. The CB1 and CB2 receptors are both G-protein coupled receptors and are involved in the inhibition of adenylate cyclase. The CB2 receptor is of particular importance due to its involvement in signal transduction in the immune system, making it a potential target for therapeutic immune intervention. A number of these selective ligands are derivatives of traditional dibenzopyran based cannabinoids. These include the very recently synthesized (2'R)- 1-methoxy-3-(2'-methylbutyl)-Δ8-THC (JWH-359) which has a 224 fold selectivity for the CB2 receptor, readily comparable to the well known 1-deoxy-3-(1',1'-dimethylbutyl)-Δ8-THC (JWH-133) which has 200 fold selectivity for the CB2 receptor. Several 9-hydroxyhexahydrocannabinols have also been synthesized and are found to be selective high affinity ligands for the CB2 receptor. These are 1-deoxy-9β-hydroxy-dimethylhexylhexahydrocannabinol (JWH-361, Ki = 2.7 nM) and 1-deoxy-9β-hydroxy-dimethylpentylhexahydrocannabinol (JWH-300, Ki = 5.3 nM). CB2 selective cannabimimetic indoles include 1-(2,3-dichlorobenzoyl)-2-methyl-3-(2-[1-morpholine]ethyl)-5-methoxyindole (L768242), (R)-3- (2-Iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole (AM1241) and 1-propyl-2-methyl-3-(1-naphthoyl) indole (JWH-015), which exhibit significant selectivity for the CB2 receptor coupled with weak affinity for the CB1 receptor. Bristol-Meyer Squibb has produced a phenylalanine derived cannabimimetic indole which possesses high CB2 affinity (Ki = 8 nM) and very low affinity for the CB1 receptor (Ki = 4000 nM). This review will discuss the current advances and recent results in the structure-activity relationships (SAR) of selective ligands for the cannabinoid CB2 receptor.

During the last decade there has been a growing interest towards the modulation of the cannabinoid CB1 receptor. The identification of CB1 cannabinoid receptor antagonists has been one of the major advances in cannabinoid research. Thus, the development of these ligands has opened new therapeutic applications. Since the discovery of the first cannabinoid receptor antagonist, rimonabant, by Sanofi in 1994, a large number of structural variations within this chemical series of 1,5-diarylpyrazoles have been described. So far, all attempts to identify novel structures for CB1 antagonists have been based on one or more pharmacophoric elements of the rimonabant structure. The advanced clinical trials of rimonabant confirm the therapeutic potential value of CB1 antagonists for the treatment of obesity. In addition, the results of pharmacological and clinical studies reveal other effective pharmacotherapeutic applications. The current review will mainly focus on the structure-activity relationships that have been established for antagonists/inverse agonists that bind to the CB1 cannabinoid receptors and on their therapeutic applications.

Monoacylglycerol lipase (MAGL) has been recently proposed as the main enzymatic activity responsible for the in vivo hydrolysis of the most abundant endocannabinoid in the brain, the 2-arachidonoylglycerol (2-AG). The endocannabinoids, mainly anandamide (AEA) and 2-AG, are a class of lipid messengers that modulate a broad number of physiological processes both in the central nervous system and in the periphery. To date, AEA has been by far the most studied endocannabinoid, although increasing evidence is pointing out the prominent, and sometimes underestimated, role of 2-AG in the regulation of different functions. Therefore, it is of outmost importance to dissect the specific cellular pathways in which these two endocannabinoids are involved. Nonetheless, little is known about the structural requirements of MAGL. Here we review the current knowledge on MAGL, with special focus on its structure and catalytic mechanism as the rational basis for the design of potent and selective compounds able to interact with it; the inhibitors that have been described to date, and the therapeutic applications that make MAGL an attractive therapeutic target.

The family of the endogenous agonists of the cannabinoid receptors - i.e., the endocannabinoids - includes several polyunsaturated fatty acid amides and esters. Arachidonoylethanolamide (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) are, respectively, the leads of these chemical families. So far, two enzymes responsible for the metabolism of AEA and 2-AG have been described: Fatty Acid Amide Hydrolase (FAAH) which hydrolyzes AEA and in some cells 2-AG, and Monoacylglycerol Lipase (MAGL) which hydrolyzes 2-AG. In spite of the early characterisation of MAGL and the nearly simultaneous clonings of the two enzymes, most of the efforts were dedicated to the study of FAAH and consequentially, the range of FAAH inhibitors available nowadays exceeds the number of compounds active upon MAGL. FAAH inhibitors can be divided in two major groups, the first one includes the inhibitors inspired by the chemical structures of FAAH substrates, which carry an arachidonoyl-, oleoyl- or palmitoyl-carbon chain that mimic the fatty acid chains of anandamide, oleamide and palmitoylethanolamide. The second group involves compounds that do not share similarities with the endocannabinoids, such as the carbamates, oxazolopyridins, 2-thioxoimidazolidin-4-ones, imidazolidine-2,4-diones and the non-steroidal anti-inflammatory drugs. However, the family of MAGL inhibitors contains few members and most of them exhibit a lack of selectivity. The purpose of this review is to give an overview of the families of synthetic inhibitors of FAAH and MAGL. The synthetic pathways, the chemical features, potencies, selectivities and modes of inhibition are listed and discussed in order to facilitate their comparison.

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