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In this issue of Recent Patents on CNS Drug Discovery, focus is laid upon the potential development of new therapeutic drugs for neurological and affective disorders through targeting the endocannabinoid system. This system of lipid mediators was discovered in the 1990's, with the cloning of cannabinoid receptors of type-1 and 2 (CB1 and CB2) - the two G-proteincoupled receptors for marijuana's major psychotropic ingredient, Δ9-tetrahydrocannabinol (THC) - and the identification of endogenous ligands for these receptors - the endocannabinoids [1]. After nearly twenty years of research on the endocannabinoid system, we now know that it plays a major role in the homeostasis of the CNS, by regulating neurotransmitter release and synaptic plasticity, at the neuronal level, and brain inflammation, at the glial cell level [2]. Several pre-clinical studies have been published strongly suggesting that cannabinoid receptor tone in the brain is activated during stress and at the onset of neurological and psychiatric disorders, in the attempt to restore homeostasis, and becomes dysfunctional (i.e. defective or overactive) in chronic diseases, such as neuroinflammatory and motor disorders, thus opening the way to the therapeutic exploitation of synthetic or natural compounds that either reinforce or reduce its actions [3].

Four articles in the present issue address these novel therapeutic strategies. First, Sagredo and colleagues [4] discuss how (endo)cannabinoid-based medicines might be beneficial for the treatment of Huntington's disease, and review at least three possible types of such medicines, i.e. 1) agents that directly target CB1 and CB2 receptors (“direct” agonists), with potential neuromodulatory/anti-excitotoxic and immune-modulatory/cytokine-targeting actions, respectively 2) agents that inhibit the degradation of endocannabinoids, and hence produce these actions in an “indirect”, and possibly more selective, manner and 3) Cannabis constituents, such as the non-psychotropic plant cannabinoid, cannabidiol, which produce their effects in a cannabinoid receptor-independent manner (e.g. through anti-oxidant and ROS-scavenging properties). The authors suggest that it will be through the combined use of more than one such mechanisms of action, in the same or different drugs, that in the future one may combat both the symptoms and the progress of Huntington's disease.

Similar (endo)cannabinoid-based approaches for the pharmacologiocal management of anxiety are reviewed also by Tambaro and Bortolato in the second article of this issue [5]. The authors also review the experimental models used preclinically for the assessement of anxiogenic- and anxiolytic-like behaviours, and also mention the emerging data with other plant cannabinoids, which, unlike THC, do not act necessarily via CB1 and CB2 receptors, as well as pharmacogenomic approaches that may allow the choice of the ideal patient to be treated with these new therapies.

Finally, the articles by Feledziak and co-authors and by Murineddu and colleagues are more medicinal chemistry-oriented and hence of great specific interest to drug developers. The former article [6] provides a comprehensive review of the properties of the hydrolytic enzymes that catalyze the inactivation not only of the endocannabinoids, anandamide and 2- arachidonylglycerol, but also of some related biologically important endogenous lipids, the pharmacological elevation of the levels of which might either interfere with or potentiate the “indirect” agonism of cannabinoid receptors. The authors provide a very useful list of patents, particularly on the inhibitors of fatty acid amide hydrolase and monoacylglycerol lipase, and of their potential indications and side effects. Murineddu et al, instead, emphasize the targeting of CB2 receptors - which is likely safer in terms of psychotropic side effects than CB1 targeting - and review the several new patents in this field, with particular focus on their use for the treatment of chronic and inflammatory pain [7].

Overall, the scenario that emerges from these four articles is that the endocannabinoid system is still regarded as a very promising field for the development of new therapeutic drugs for the treatment of CNS disorders [8], although the authors also emphasize the several challenges that clinicians, pharmacologists and medicinal chemists will have to face in this effort, due to the complex and multi-faceted nature of endocannabinoid action and dysregulation in the brain [9].
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Document Type: Research Article

Publication date: 2012-04-01

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  • Recent Patents on CNS Drug Discovery publishes review articles on recent patents in the field of CNS drug discovery e.g. novel bioactive compounds, analogs & targets. A selection of important and recent patents on CNS drug discovery is also included in the journal. The journal is essential reading for all researchers involved in CNS drug design and discovery.
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