Recent Patents on CNS Drug Discovery (Discontinued) - Volume 7, Issue 1, 2012

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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Pain, a homeostatic and protective mechanism which can go awry in disease states and therefore needs treatment, is a complex and differentiated sensorial perception which may be classified as physiological, inflammatory and neuropathic. Chronic pain represents a major health problem throughout the world, thus several companies and researchers have embarked on the search for new drugs and targets to treat the disease. The different types of receptors in the CNS involved in the mediation of analgesia include the cannabinoid receptors: in particular, CB2 modulators seem to represent a new potential class of analgesic. This review covers recent patents and advances in CB2 agonist studies in the management of pain.

Rich evidence has shown that cannabis products exert a broad gamut of effects on emotional regulation. The main psychoactive ingredient of hemp, Δ9-tetrahydrocannabinol (THC), and its synthetic cannabinoid analogs have been reported to either attenuate or exacerbate anxiety and fear-related behaviors in humans and experimental animals. The heterogeneity of cannabis-induced psychological outcomes reflects a complex network of molecular interactions between the key neurobiological substrates of anxiety and fear and the endogenous cannabinoid system, mainly consisting of the arachidonic acid derivatives anandamide and 2-arachidonoylglycerol (2-AG) and two receptors, respectively termed CB1 and CB2. The high degree of interindividual variability in the responses to cannabis is contributed by a wide spectrum of factors, including genetic and environmental determinants, as well as differences in the relative concentrations of THC and other alkaloids (such as cannabidiol) within the plant itself. The present article reviews the currently available knowledge on the herbal, synthetic and endogenous cannabinoids with respect to the modulation of anxiety responses, and highlights the challenges that should be overcome to harness the therapeutic potential of some of these compounds, all the while limiting the side effects associated with cannabis consumption. In addition the article presents some promising patents on cannabinoid-related agents.

Cannabinoid pharmacology has experienced a notable increase in the last 3 decades which is allowing the development of novel cannabinoid-based medicines for the treatment of different human pathologies, for example, Cesamet ® (nabilone) or Marinol® (synthetic Δ9-tetrahydrocannabinol for oral administration) that were approved in 80s for the treatment of nausea and vomiting associated with chemotherapy treatment in cancer patients and in 90s for anorexiacachexia associated with AIDS therapy. Recently, the british company GW Pharmaceuticals plc has developed an oromucosal spray called Sativex®, which is constituted by an equimolecular combination of Δ9-tetrahydrocannabinol- and cannabidiol- enriched botanical extracts. Sativex® has been approved for the treatment of specific symptoms (i.e. spasticity and pain) of multiple sclerosis patients in various countries (i.e. Canada, UK, Spain, New Zealand). However, this cannabis- based medicine has been also proposed to be useful in other neurological disorders given the analgesic, antitumoral, anti-inflammatory, and neuroprotective properties of their components demonstrated in preclinical models. Numerous clinical trials are presently being conducted to confirm this potential in patients. We are particularly interested in the case of Huntington's disease (HD), an autosomal-dominant inherited disorder caused by an excess of CAG repeats in the genomic allele resulting in a polyQ expansion in the encoded protein called huntingtin, and that affects primarily striatal and cortical neurons thus producing motor abnormalities (i.e. chorea) and dementia. Cannabinoids have been studied for alleviation of hyperkinetic symptoms, given their inhibitory effects on movement, and, in particular, as disease-modifying agents due to their anti-inflammatory, neuroprotective and neuroregenerative properties. This potential has been corroborated in different experimental models of HD and using different types of cannabinoid agonists, including the phytocannabinoids present in Sativex®, and we are close to initiate a clinical trial with this cannabis-based medicine to evaluate its capability as a disease-modifying agent in a population of HD patients. The present review will address all preclinical evidence supporting the potential of Sativex® for the treatment of disease progression in HD patients. The article presents some promising patents on the cannabinoids.

Endocannabinoids are lipid transmitters binding and activating the cannabinoid receptors. Both cannabinoid receptors and endocannabinoids, such as 2-arachidonoylglycerol and anandamide, have been shown to control numerous physiological and pathological processes, including in the central nervous system. Thus regulating endocannabinoid levels in-vivo represents an interesting therapeutic perspective in several CNS-related diseases. To date four enzymes - Fatty Acid Amide Hydrolase (FAAH), N-Acylethanolamine-hydrolyzing Acid Amidase (NAAA), Monoacylglycerol Lipase (MAGL), α/β-Hydrolase Domain 6 (ABHD6) - were shown to control endocannabinoid levels in tissues or in intact cells. While the searches for NAAA and ABHD6 inhibitors are still in their beginning, a growing number of selective and potent inhibitors are now available to inhibit FAAH and MAGL activities. Here, based on the literature and patent literature, we review the compounds of the different chemical families that have been developed to inhibit these enzymes, with a special emphasis on FAAH and MAGL inhibitors.

Nanotechnology exerts an increasing impact on the development of more effective tools for the diagnosis and treatment of human diseases. This applies in particular to central nervous system (CNS) disorders. Development of therapeutics for CNS is, in fact, one of the most challenging areas in drug development, mainly due to the presence of the blood-brain barrier (BBB) which separates the blood from the cerebral parenchyma thus limiting the brain uptake of the vast majority of neurotherapeutic agents. Among the several strategies which have been developed over the last years in order to overcome this problem, nanotechnology-based approaches have gained increasing attention as the most promising strategies for CNS targeted drug delivery. Nanocarriers offer several advantages such as the possibility to maintain drug levels in a therapeutically desirable range, as well as the increase of half-lives, solubility, stability and permeability of drugs. Furthermore, the system can be designed in such a way as to release the drug in a controlled way or in a triggered way. This review focuses on lipid-based nanocarriers and more specifically on liposomes, lipid-core micelles, and lipid nanocapsules, and provides an update on their composition and use, including recent patents in the field.

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