The Medicinal Chemistry Of Agents Targeting The Endogenous Cannabinoid System

Jacob Bell

New Member
Outi M. H. Salo-Ahen


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.
Affiliation: EML Research gGmbH Schloss-Wolfsbrunnenweg 33 D-69118 Heidelberg,Germany.

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