Recent Patents on CNS Drug Discovery (Discontinued) - Volume 4, Issue 2, 2009

In recent years, one of the major advances in terms of our understanding of the pathology underlying many neurological conditions has been the realisation that inflammation may play a major role in many acute and chronic conditions. Inflammation is not only involved in acute CNS conditions, such as stroke and traumatic injury, but it is also a central factor in chronic and neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease and multiple sclerosis. There are some key differences between inflammatory processes within the CNS (neuroinflammation) and peripheral inflammation, partly due to the natural compartmentation of the brain by the blood-brain barrier. As a result of these differences, the classical anti-inflammatory agents (steroids and NSAIDs) have not played a major role in the management of CNS inflammatory conditions. In order to address this clinical need, there is significant interest in developing novel anti-inflammatory agents that may help prevent or ameliorate CNS inflammation. In this review, the authors focus on disclosures from the patent literature to give a broad overview of the different approaches that are being taken to try and develop more effective and selective anti-inflammatory agents to manage acute and chronic inflammation in the CNS. A variety of approaches are discussed including modulating the activity of various inflammatory mediators such as cytokines, chemokines and kinins, targeting toll-like receptors as a possible therapeutic intervention, and novel approaches to managing the actions of eicosanoids in neuroinflammation.

Voltage-dependent Ca2+ channels (VDCCs) play important roles in physiological functions and pathological processes of the nervous system. Given that the precise regulation of Ca2+ signaling is important for neuronal processes such as action potential generation, transmitter release, and synaptic plasticity, alterations in Ca2+ current through VDCCs affect the functions of neurons and circuits. Central nervous system (CNS) diseases, including pain, epilepsy, seizure, anxiety, depression, dementia, and stroke, are characterized by an altered balance between excitatory and inhibitory neuronal functions. An efficient way of controlling such diseases is to block or modulate VDCC function. An effective strategy to reduce the likelihood of adverse effects is to develop agents that selectively control the VDCC isoform/subunit involved in the mechanism of the disease in question. This review provides an overview of knowledge on VDCCs, traditional and newly developed therapeutic fields, clinical fields, and the diverse medicinal chemistry of traditional and newly developed VDCC blockers in the CNS based on the scientific and patent literature.

Naturally occurring cannabinoids (phytocannabinoids) are biosynthetically related terpenophenolic compounds uniquely produced by the highly variable plant, Cannabis sativa L. Natural and synthetic cannabinoids have been extensively studied since the discovery that the psychotropic effects of cannabis are mainly due to Δ9-THC. However, cannabinoids exert pharmacological actions on other biological systems such as the cardiovascular, immune and endocrine systems. Most of these effects have been attributed to the ability of these compounds to interact with the cannabinoid CB1 and CB2 receptors. The FDA approval of Marinol® , a product containing synthetic Δ9-THC (dronabinol), in 1985 for the control of nausea and vomiting in cancer patients receiving chemotherapy, and in 1992 as an appetite stimulant for AIDS patients, has further intensified the research interest in these compounds. This article reviews patents (2003-2007) that describe methods for isolation of cannabinoids from cannabis, chemical and chromatographic methods for their purification, synthesis, and potential therapeutic applications of these compounds.

L-Arginine is a basic amino acid that has versatile metabolic roles, being involved in the generation of a wide range of biologically active intermediates such as nitric oxide (NO), polyamines, creatine and L-amino acids [1]. Because the levels of L-arginine reflect a metabolic crossroads, the mechanisms of its synthesis and degradation in peripheral tissues are very well described. However, there is an increasing amount of data also implicating this amino acid as a mediator of central nervous system activities and those are not yet fully understood. Here we shall summarize the tissuespecific pathways controlling L-arginine intracellular and blood levels and also the emerging evidence pointing to a role of this metabolite in the central regulation of diverse physiological processes, as blood pressure control and inflammatory response. As a conclusion we shall discuss the advantages of targeting L-arginine metabolism over other NO donors, as a general strategy to correct NO deficiency related diseases and discuss a few new patents recently deposited which take into account the rational perspective outlined in the present review.

Alzheimer's disease is one of the most challenging threats to the healthcare system in society. One of the main characteristic of Alzheimer's disease (AD) pathology is formation of amyloid plaques from accumulation of amyloid beta peptide. The therapeutic agents that are currently available for AD including acetylcholinesterase inhibitors (AchEIs) and the N-methyl-D-aspartate (NMDA) antagonist are focused on improving the symptoms and do not revert the progression of the disease. This limitation coupled with the burgeoning increase in the prevalence of AD and resultant impact on healthcare economics calls for more substantial treatments for AD. According to the leading amyloid hypothesis, cleavage of amyloid precursor protein to release amyloid beta peptide is the critical event in pathogenesis of Alzheimer's disease. Recently treatment strategies have been focused on modifying the formation, clearance and accumulation of neurotoxic amyloid beta peptide. This article reviews different therapeutic approaches that have been investigated to target amyloid beta ranging from secretase modulators, antiaggregation agents to amyloid immunotherapy. Authors review the different novel drugs which are in clinical trials.

Treatment of mood disorders is one of the most challenging territories in elderly. Effectiveness of different treatment strategies could be related to age, sex and physical conditions. The side effect profile in this population also affects pharmacological interventions. Our review includes the neurostimulative treatment strategies in elderly. However, possible treatment strategies such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS) and deep brain stimulation (DBS) were less studied in elderly. ECT was found to be an effective treatment procedure in mood disorders. Few double-blind sham controlled studies were conducted and demonstrated effectiveness of TMS. DBS has lack of double-blind studies. ECT seems to be the golden standard for the treatment resistant elderly patients, yet side effect profile of ECT in elderly will be discussed. Double -blind sham controlled studies with larger samples are necessary to confirm preliminary results with transcranial direct current stimulation (tDCS), magnetic seizure therapy (MST) and VNS, DBS.

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