Although currently prescribed antidepressants with actions mediated through alteration of monoaminergic transmission have been proven to be useful for the treatment of depressive and anxiety disorders, they are far from ideal due to their slow onset of action and low rate of responses. Although the brain monoamine systems have long been the focus of drug therapy for depression and anxiety disorders, current drug discovery has aimed at new molecular targets outside the monoamine systems to overcome these problems. Recent increase in understanding of the molecular mechanisms of depression and anxiety has provided alternative molecular targets for these disorders. In particular, receptors within the glutamate, γ-aminobutyric acid and neuropeptide systems provide a diversity of drug targets, and molecular biological and behavioral studies of these receptors have revealed the important roles they play in depression and anxiety. Here, we review recent patents and advances in research on these emerging molecular targets for the treatment of depression and anxiety, and discuss their advantages over currently used antidepressants and anxiolytics.
Tianeptine, an atypical antidepressant patented and developed by Servier, enhances the synaptic reuptake of serotonin, without affecting norepinephrine and dopamine uptake, while it lacks affinity for neurotransmitter receptors. This mechanism for an antidepressant is apparently paradoxical, since the currently employed antidepressants enhance serotonin by inhibiting its breakdown or by inhibiting monoaminergic reuptake. Although tianeptine has been shown to reduce central 5HT availability and to indirecty modulate central adrenergic and dopaminergic systems and to indirectly inhibit cholinergic hyperactivity, its antidepressant action is believed to be more directly related to central neuronal remodeling and restoration of neuronal plasticity. In reliable animal models of depression tianeptine has been shown to prevent neurodegeneration and decreases in hippocampal volume in response to chronic stress. These effects on neuroplasticity are suspected to involve the normalization of the hypothalamic-pituitary-adrenal axis and modulatory effects on excitatory amino acids and N-methyl-D-aspartate receptors. Together with a body of related studies, these data provide further support for the hypothesis that depression may involve dysregulation of pathways controlling cellular resilience and that treatment should be directed towards the reversal thereof. Importantly, tianeptine is not anxiogenic and has also been shown to be effective in treatment-resistant depression, which may lead the way to a major breakthrough in the treatment of depression.
Multiple lines of evidence suggest that a dysfunction in the glutamatergic neurotransmission via the N-methyl- D-aspartate (NMDA) receptors contributes to the pathophysiology of psychiatric diseases including schizophrenia. The potentiation of NMDA receptor function may be a useful approach for the treatment of diseases associated with NMDA receptor hypofunction. One possible strategy is to increase synaptic levels of glycine by blocking the glycine transporter-1 (GlyT-1) in glia cells, since glycine acts as a co-agonist site on the NMDA receptor. In this article, the author reviews the recent important patents on GlyT-1 inhibitors for treatment of schizophrenia and other psychiatric diseases associated with the NMDA receptor hypofunction.
Spinal cord injuries devastate the lives of those affected. Normally, acute injury leads to chronic injury in the spinal cord, although this has a variable impact on normal sensory and motor functions. Currently the only drug used to treat acute spinal cord injury is methyl-prednisolone, administered in order to prevent secondary inflammatory neural damage. Thus, it is time that alternative and complementary pharmacological, cell and gene therapies be developed. In order to achieve this, several approaches to stimulate spinal cord repair must be considered. Indeed, the main lines of research that have been established in different animal models of spinal cord regeneration are now beginning to produce encouraging results. Several patents have been derived from these studies and hopefully, they will lead to the development of new treatments for human spinal cord injuries. Here is presented a review of the main patents that have been generated by this research, and that can be classified as: Patents involving the use of different factors that promote axonal regeneration. Patents aimed at overcoming the activity of glial scar inhibitory molecules that hinder axonal regeneration. These approaches can be further subdivided into those that block Nogo and other myelin components, and those that involve the use of chondroitinase against glial scar chondroitin sulphate proteoglycans. Patents concerning glial cell therapy, in which glial cells are used to mediate axonal repair in the spinal cord (Schwann cells, olfactory ensheathing cells or astrocytes).
The vanilloid receptor (TRPV1) is a member of the transient receptor potential family of ion channels that is highly expressed in nociceptive primary afferent sensory neurons. TRPV1 is a voltage-dependent cation channel, which can be activated at physiological membrane potentials by stimuli including noxious heat ( > 42 degrees), capsaicin, hydrogen ions and anandamide. Activation of TRPV1 results in release of neurotransmitters from peripheral and central nerve terminals, resulting in pain and inflammation. Endogenous inflammatory mediators also promote activation of TRPV1. Studies in TRPV1 null mice reveal that responses to noxious heat stimuli are normal but the development of thermal hyperalgesia is abolished. Several TRPV1 antagonists have recently been developed and reported to alleviate or reverse mechanical and thermal hyperalgesia associated with inflammatory pain. This review will examine the development of patented TRPV1 antagonists as a potential clinical treatment for the alleviation of pain associated with hyperalgesia and inflammation.
Difficulties with delivery of functional enzyme to the brain limit the ability to modify neurologic outcome in patients with neuronopathic forms of the lysosomal storage diseases. In a subset of these disorders, which result from a disruption of glycosphingolipid metabolism, the use of a small molecule inhibitor of substrate precursor synthesis may reduce the amount of brain tissue lipid deposition and lead to amelioration of disease. The efficacy of this approach, termed substrate reduction therapy, has been demonstrated in several animal models; with resultant reduction of ganglioside storage in the brain, delayed onset of symptoms and prolonged survival. This pre-clinical proof of therapeutic concept served as the rationale for proceeding with trials in humans using miglustat; an imino-sugar inhibitor of ceramide-specific glucosytransferase (the catalyst for the first committed step in glycosphingolipid synthesis). The glycosphingolipidoses are rare orphan disorders; the limited number of suitable study subjects and the paucity of information on the natural history of these disorders represent major hurdles in the conduct of clinical trials. As treatment potentially constitutes lifelong administration, there will be a need to identify any potential safety considerations attendant to the use of these agents. With greater understanding of disease mechanism, adjunctive therapies may be identified; offering the prospect of modifying these otherwise relentlessly progressive neurodegenerative diseases.
Several Voltage-Gated Sodium Channels (VGSC) are widely expressed on lymphocytes and macrophages but their role in immune function is still debated. Nevertheless, Na+ influx through VGSC is required for lymphocytes activation and proliferation, since these responses are blocked by Na+-free medium or by VGSC blockers. These effects may be mediated by the reduced intracellular Na+ levels, which in turn may impair the activity of Na+/Ca++ exchanger resulting in reduced intracellular Ca++ levels during lymphocyte activation. Furthermore, in Jurkat cell line VGSC appear to be involved in cell volume regulation, migration in artificial matrix and cell death by apoptosis. VGSC play a role in macrophage function as well, and VGSC blockers impair both phagocytosis and inflammatory responses. Several VGSC blockers have shown immunomodulatory properties in mice models, skewing the immune response toward a Th2- mediated response, while suppressing Th1-mediated responses, and VGSC already used in clinical practice are known to modulate immunoglobulin (Ig) levels both in mice and in humans. These effects suggest that VGSC blockers may find clinical application in the treatment of autoimmune and inflammatory disease. However, many of these drugs induce a number of severe side effects. The relevance of VGSC function in immune regulation suggest that the testing of newly patented VGSC blockers for their effect on immunity may be worthwhile.
Long-term use of benzodiazepines as hypnotics, anxiolytics, anticonvulsants and muscle relaxing drugs is jeopardized by adverse effects on memory, addictive properties, and development of tolerance. Major efforts have gone into developing benzodiazepine-like drugs that are more selective in their therapeutic effect, have additional uses and/or lack the adverse effects of benzodiazepines. The reviewed prototype patent exemplifies such efforts. Newer drugs are thought to act selectively on one of the two neuronal benzodiazepine receptors, on the astrocytic mitochondrial benzodiazepine receptor and/or on GABAA/benzodiazepine receptor complexes displaying specific subunits. It is overlooked that astrocytes also express benzodiazepine receptors that enhance depolarization-mediated entry of Ca2+ by interacting with membrane-associated GABAA-like receptors, mediating depolarization because of a high Clconcentration within astrocytes. The resulting increase in free cytosolic Ca2+, which stimulates glycogenolysis, is inhibited not only by the peripheral-type benzodiazepine antagonist PK11195 but also by the neuronal antagonist flumazenil. Increasing awareness of the role(s) of astrocytic Ca2+ homeostasis and energy metabolism for CNS function suggests that activation of this receptor might contribute to both therapeutic and adverse effects of benzodiazepine-like drugs. This receptor should be kept in mind when developing and testing new drugs; in turn these drugs may help elucidating its functional role.
(-)-Galanthamine is a selective, reversible competitive acetylcholinesterase inhibitor that has been recently approved for the symptomatic treatment of Alzheimers disease. Galanthamine is a natural product belonging to the Amaryllidaceae family of alkaloids. The pharmacological history of galanthamine shows that the bioactive compound was discovered accidentally in the early 1950s, and the plant extracts were initially used to treat nerve pain and poliomyelitis. In addition, galanthamine had since been tested for use in anesthesiology, from facial nerve paralysis to schizophrenia. Galanthamine is a long-acting, selective, reversible and competitive AChE inhibitor that has recently been tested in AD patients and found to be readily absorbed, to be a performance enhancer on memory tests in some patients, and to be well tolerated, although some cholinergic side effects were observed. A number of total synthetic approaches have been reported, and a method for the industrial scale-up preparation of galanthamine is now being developed and patented. A variety of galanthamine derivatives have also been synthesized aiming to develop an agent free from cholinergic adverse effects. Galanthamine is a natural product that complements other synthetic drugs for the management of AD. In this account we will review the recent patent literature showing the most important advance on the chemistry of galanthamine.
GABA (γ-aminobutyric acid) is one of the major inhibitory transmitters in the central nervous system of mammals. GABA is not transported efficiently into the brain from the bloodstream (i.e. GABA does not effectively cross the blood-brain barrier). Consequently, brain cells provide virtually all of the GABA found in the brain i.e. GABA is biosynthesized by decarboxylation of glutamic acid with pyridoxal phosphate. The implication of low GABA levels in a number of common CNS disease states and/or common medical disorders has stimulated intensive interest in preparing GABA analogs, which have superior pharmaceutical properties in comparison to GABA. Accordingly, a number of GABA analogs, with considerable pharmaceutical activity have been synthesized in the art. This review includes some of the important recent patents on novel GABA analogs and some pharmaceutical compositions there of.
It is now almost a century ago that Alois Alzheimer first presented his results in public. Main characteristics of Alzheimers disease (AD) are massive cerebral accumulation of amyloid, composed of fibrillary aggregates of the Amyloid beta peptide (Aβ) and intracellular accumulation of abnormally phosphorylated tau protein associated with widespread neurodegeneration. The clinical picture is characterized by progressive and irreversible dementia, which is eventually fatal. To date, there is no cure for this severe disease affecting more than of 30 million individuals worldwide. In the last decades, the treatment of Alzheimer patients was mainly focusing on symptomatical strategies. Based on the augmented knowledge about the mechanisms underlying the pathology of AD, particularly the molecular causes and consequences of AD, different therapeutic approaches arose and recently, treatment with Statins, NSAIDs and Aβ vaccines reached the level of clinical trials, showing some indication of efficacy already. According to actual evaluations, these approaches have realistic chances to become established as therapeutic routine in AD within the next 10 years. We will review here some of the most promising novel approaches to cure and prevent rather than to treat the symptoms of AD.