Showing papers in "Recent Patents on Cns Drug Discovery in 2006"

Therapeutic potential of adult neural stem cells.

Abstract: The central nervous system (CNS) elicits limited capacity to recover from injury. Though considerable efforts and means have been deployed to find treatments for neurological diseases, disorders and injuries, there is still no cure for these ailments, and new alternatives for therapy must be explored. Because they generate the main phenotypes of the nervous system, neural stem cells (NSCs) hold the promise to cure a broad range of neurological diseases and injuries. With the confirmation that neurogenesis occurs in the adult brain and NSCs reside in the adult CNS, new treatments for neurological diseases and injuries are being considered. Particularly, the transplantation of adult-derived neural progenitor and stem cells to restore brain functions. In this manuscript, we will review the recent developments in adult neurogenesis and NSCs, and patent applications filed in relation to discoveries made in this new field of research.

Galanthamine, a natural product for the treatment of Alzheimer's disease.

Abstract: (-)-Galanthamine is a selective, reversible competitive acetylcholinesterase inhibitor that has been recently approved for the symptomatic treatment of Alzheimer's 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.

Neuropeptide Y as an endogenous antiepileptic, neuroprotective and pro-neurogenic peptide.

Abstract: Neuropeptide Y (NPY) is a small peptide important in cardiovascular physiology, feeding, anxiety, depression and epilepsy. In the hippocampus, NPY is mainly produced and released by GABAergic interneurons and inhibits glutamatergic neurotransmission in the excitatory tri-synaptic circuit. Under epileptic conditions, there is a robust overexpression of NPY and NPY receptors particularly in the granular and pyramidal cells, contributing to the tonic inhibition of glutamate release and consequently to control the spread of excitability into other brain structures. Recently, an important role was attributed to NPY in neuroprotection against excitotoxicity and in the modulation of neurogenesis. In the present review we discuss the potential relevance of NPY and NPY receptors in neuroprotection and neurogenesis, with implications for brain repair strategies. Recent patents describing new NPY receptor antagonists directed to treat obesity and cardiovascular disorders were published. However, the NPYergic system may also prove to be a good target for the treatment of pharmaco-resistant forms of temporal lobe epilepsy, by acting on hyperexcitability, neuronal death or brain repair. In order to achieve new NPY-based antiepileptic and brain repair strategies, selective NPY receptor agonists able to reach their targets in the epileptic brain must be developed in the near future.

Glycine transporter inhibitors as therapeutic agents for schizophrenia.

Abstract: 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.

Tianeptine: A Novel Atypical Antidepressant that May Provide New Insights into the Biomolecular Basis of Depression

Abstract: 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.

TRPV1 antagonists as a potential treatment for hyperalgesia.

Abstract: 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.

Selective Dopamine D3 Receptor Antagonists: A Review 2001-2005

Abstract: A growing body of evidence indicates that dopamine (DA) D(3) receptors are significantly involved in the control of drug-seeking behavior, and may play an important role in the pathophysiology of impulse control disorders and schizophrenia. This hypothesis has been difficult to test due to the lack of compounds with high selectivity for central DA D(3) receptors. Recently, however, the synthesis and characterization of new highly potent and selective DA D(3) receptor antagonists has permitted to characterize the role of the DA D(3) receptor in a wide range of preclinical animal models. Although the proof of efficacy of pharmacotherapeutic agents is to be derived ultimately from clinical trials, the preclinical findings that selective antagonism at DA D(3) receptors reduces the reinforcing efficacy of drugs of abuse, reverses cognitive deficits, and shows efficacy in animal models of schizophrenia add to an accumulating body of evidence that selective DA D(3) receptor antagonists may hold highest promise in the treatment of several neuropsychiatric diseases. The present review is aiming at describing current areas of interest and the possible future development of selective DA D(3) receptor antagonists by outlining about 40 patents and 100 publications in this research field between 2001 and 2005.

Non-monoamine-based approach for the treatment of depression and anxiety disorders.

Abstract: 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.

An update on GABA analogs for CNS drug discovery.

Abstract: 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.

Voltage-Gated Sodium Channel Blockers as Immunomodulators

Abstract: 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.

Therapeutic perspectives in Alzheimer's disease.

Abstract: It is now almost a century ago that Alois Alzheimer first presented his results in public. Main characteristics of Alzheimer's disease (AD) are massive cerebral accumulation of amyloid, composed of fibrillary aggregates of the Amyloid beta peptide (Abeta) 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 Abeta 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.

The hypothalamus and obesity.

Abstract: Obesity has reached epidemic proportions across the developed world. Even though there have been numerous scientific advances in terms of the understanding of the regulation of energy homeostasis, few novel anti-obesity drugs have emerged. Furthermore, those that are available have limited efficacy in producing and maintaining a weight loss beyond 10%. This is partly attributable to the complex neuronal circuitry at play within the central nervous system and periphery, which acts to regulate food intake and energy expenditure. This article will focus on a selection of the many products (peptides, neurotransmitters and others) such as endocannabinoids, Neuropeptide Y, Orexins, Melanin-Concentrating Hormone, Melanocortins, Cocaine and Amphetamine Regulated Transcript and Serotonin, expressed within the brain, that have been shown to influence energy balance. The true relevance of many of these to the regulation of human energy balance remains uncertain, but some novel anti-obesity drugs aimed at these targets are likely to emerge in the next few years.

In search of novel AMPA potentiators.

Abstract: Glutamate is the major excitatory neurotransmitter in the brain. Amongst ionotropic receptors responding to glutamate, the AMPA subtype has been considered as essential for the fast excitatory neurotransmission in the central nervous system and the expression and maintenance of long-term potentiation. As glutamate is known to be involved in many neurological and psychiatric disorders, AMPA receptors seem to represent interesting targets to develop therapeutic drugs. Hence, the enhancement of AMPA signals is an approach currently investigated for the management of Alzheimer's disease, schizophrenia or mood disorders. In particular, many efforts are being conducted in the development of AMPA positive allosteric modulators ("potentiators"), which alter the rate of receptor desensitization. The major chemical families developed as AMPA potentiators are aniracetam derivatives, cyclothiazide derivatives and biarylpropylsulfonamides derivatives.

AMPA receptor antagonists: potential therapeutic applications.

Abstract: The current review will focus on the recent patents for AMPA receptor antagonists and their claims, evidence for their therapeutic effectiveness in the treatment of epilepsy and their potential role in psychiatric and neurodegenerative disorders. It will also highlight the proposed mechanisms of action and the implications thereof for our current understanding of the biomolecular basis of these pathologies. It will conclude with a summary of what we know, but also point out the remaining uncertainties, especially as this relates to the claims in the patent under discussion.

The quest to repair the damaged spinal cord.

Abstract: 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).

Miglustat: substrate reduction therapy for lysosomal storage disorders associated with primary central nervous system involvement.

Abstract: 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.

The Astrocytic GABAA/Benzodiazepine-Like Receptor: The Joker Receptor for Benzodiazepine-Mimetic Drugs?

Abstract: 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 GABA(A)/benzodiazepine receptor complexes displaying specific subunits. It is overlooked that astrocytes also express benzodiazepine receptors that enhance depolarization-mediated entry of Ca(2+) by interacting with membrane-associated GABA(A)-like receptors, mediating depolarization because of a high Cl(-) concentration within astrocytes. The resulting increase in free cytosolic Ca(2+), 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 Ca(2+) 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.

Protein kinase C pharmacology: perspectives on therapeutic potentials as antidementic and cognitive agents.

Abstract: Activity of protein kinase C (PKC) isozymes plays a critical role in various types of learning and memory. In addition, abnormal functions of PKC signal cascades in neurons represent one of the earliest changes in the brains of patients with Alzheimer's disease (AD) and dementia related to ischemic/stroke events. In preclinical studies, inhibition or impairment of PKC activity leads to compromised learning and memory, whereas an appropriate activation of PKC isozymes has been found to enhance learning and memory and/or to produce antidementic effects. The PKC activators not only increase activity of PKC isozymes and thereby restore PKC signaling activity but also reduce the accumulation of neurotoxic amyloid and tau protein hyperphosphorylation in the brain. These observations strongly suggest that PKC pharmacology may represent an attractive area for the development of cognitive therapeutics and agents against dementia in the future.

Reading and writing the blood-brain barrier: relevance to therapeutics.

Abstract: The blood-brain barrier (BBB) serves to protect the central nervous system (CNS) from damage by exogenous molecules. In doing so, it also can prevent some drugs from reaching their sites of action. Accordingly, a variety of methods for bypassing the BBB have been developed. Ekwuribe et al. recently patented a method for drug conjugation in order to increase lipophilicity, and therefore BBB permeability. Shalev developed a device for opening the barrier via parasympathetic nerve fiber stimulation and Gudkov et al. produced compounds that modulate the activity of multidrug transporter proteins, by either increasing or decreasing the selective permeability of the BBB. A variety of CNS disorders contribute to barrier disruption, and detection of this opening can be used for both diagnostic purposes and for determining time periods when drugs can more easily enter the CNS. While expensive and time-consuming imaging techniques are currently used for this purpose, Janigro et al. have devised a method for detecting plasma levels of S100beta, a peripheral protein marker for BBB disruption. These techniques for both "reading" and "writing" the BBB will help new and old medications to reach their pharmacological targets in the CNS.

Development of new drugs that act through membrane receptors and involve an action of inverse agonism.

Abstract: Synaptic transmission and, consequently, neurological processes are regulated by neurotransmitters and other neuro-modulators that recognize specific receptors. There are two main families of receptors that are targets for most of the compounds which act in the central nervous system (CNS); ion channel coupled receptors and G-protein coupled receptors (GPCR). The drugs that act through these receptors and are used for the treatment of different diseases related with the CNS, have traditionally been classified as agonists or antagonists. However, since the discovery of the constitutive activity of some neurotransmitter receptors during the eighties, the inverse agonist drugs have emerged as a new group of bioactive compounds with the ability to decrease receptor basal activity. New experimental evidence indicates that pathologies associated with different diseases that affect the CNS physiology could involve constitutively active receptors. Therefore, different methods and systems have been patented to explore the receptors that show high basal activity and to test the decrease of the receptor activity produced by inverse agonist compounds. In recent years some inverse agonist drugs and their targets have been patented which are capable of treating CNS related disorders. These include inverse agonists that are selective for serotonin or histamine receptors aimed at treating neuropsychiatric disorders, cannabinoids with an anorexigenic effect and inverse agonists selective for gabaergic receptors for the treatment of neurodegenerative or cognitive disorders.

Phosphorylation-dephosphorylation imbalance of cytoskeletal associated proteins in neurodegenerative diseases.

Abstract: Neurons are highly asymmetric cells, specialized to transmit and receive information through axons and dendrites. Neuronal morphology is determined by a particular cytoskeletal organization that provides the framework for distinct axonal and dendritic structures. Dynamic cytoskeletal rearrangements occur during neurite outgrowth, neuronal plasticity and synaptic connectivity. In this work, we summarize the evidences that support that these dynamic changes are mainly governed by phosphorylation-dephosphorylation equilibrium of cytoskeleton and cytoskeletal-associated proteins. In addition, we describe evidence supporting that in neurodegeneration an imbalance of this equilibrium occurs, followed by disarray of the cytoskeleton in axons and dendrites with the consequent disruption of synaptic connectivity. Finally we discuss current strategies and patents that could contribute to re-establish a balance in the brain of patients with dementia.

Recent developments in anxiety disorders.

Abstract: Anxiety disorders are common and debilitating mental illnesses. Current pharmacological treatments are beset by problems of poor efficacy and side effect profiles. Increasing understanding of novel neurotransmitter systems and the interplay between these systems is broadening the scope of anxiolytic drug treatment. This article aims to describe the areas of current interest and possible future development of anxiolytic drugs by outlining recent patents in this field. A patent database was searched for 17 neurotransmitters and their synonyms as well as 23 compounds of recent known interest from May 2003 to May 2005. The internet resources Pubmed and Google Scholar were searched for peer reviewed literature using the same search parameters. Results were grouped into neurotransmitter systems to present an overview of recent developments in the neuropharmacology of anxiety disorders.

A review of agents patented for their neuroprotective properties.

Abstract: The brain continues to remain an area where little corrective surgery can be performed. Recently, the ability to reverse some brain damage and perhaps prevent further damage has moved closer to hospitals and clinics. Several agents demonstrating neuroprotective properties and even neural regeneration have been developed to the extent that they have been granted patent protection, one of the first steps in commercial development. The concept of neuroprotection is the administration of an agent that can reverse some of the damage or prevent further damage. Some agents offer protection against cell degeneration due to oxidative stress whilst other agents specifically protect against neural stroke damage. In the early years of neuroprotective research, most compounds were not designed as such but were found to possess neuroprotective activity in later studies. However, the original structures have since become the leads for purely synthetic derivatives. Most of the agents are or were designed from biologically active natural products, either plant extracts or endogenous peptides/proteins and even sequences of RNA. This review will present the most recently patented neuroprotective agents.

Halogenated Derivatives of Aromatic Amino Acids Exhibit Balanced Antiglutamatergic Actions: Potential Applications for the Treatment of Neurological and Neuropsychiatric Disorders

Abstract: Glutamate, the major excitatory neurotransmitter, is critical for normal brain development and function. Both extremes of glutamate receptor activity are detrimental for the brain. Glutamates role in excitotoxicity has driven the search for receptor antagonists as neuroprotective agents, most of which have failed to achieve clinical, i.e. efficacious and safe, neuroprotection. High selectivity and potency provide potential explanations for this failure. For example, targeting individual glutamate receptor subtypes leaves other pathways of glutamatergic excitotoxicity intact. Furthermore, potent depression of glutamate receptor activity causes clinical side effects, such as the symptoms of schizophrenia produced by NMDA receptor antagonists. To produce efficacious neuroprotection devoid of significant side effects, it may be necessary to normalize the function of all components of the glutamatergic system, instead of blocking a single type of glutamate receptors. Halogenated derivatives of aromatic amino acids modulate glutamatergic activity via multiple pre- and postsynaptic actions with moderate efficacy. In addition, these compounds may trap hydroxyl radicals and facilitate hydroxyl radical-impaired glutamate uptake. Their balanced polyvalent action may overcome the limitations of previously tested glutamatergic agents and provide a basis for their use in the treatment of neurological and neuropsychiatric disorders. The properties of this class of compounds and relevant patents are reviewed in this article.

Recent patents on pharmacotherapy for alcoholism.

Abstract: Alcohol use disorders represent a substantial public health problem all over the world affecting approximately 2 billion alcohol users worldwide as estimated by the WHO in 2000. Given the harmful effects of alcohol on the distressed individuals and society as a whole, there is an increasing urge for the development of new, more efficient medications. Although, investigation of the mechanisms underlying the actions of ethanol in the central nervous system has been ongoing for more than a century, the exact mechanism by which ethanol exerts its effect is still a matter of debate. In recent years, scientists discovered evidence that alcohol acts on several neurotransmitter systems in the brain to create its alluring effects. Besides altering the release of neurotransmitters like dopamine, ethanol alters the function of a number of neurotransmitter receptors as well as transporters. When ethanol is used for longer period of time, changes in these specific neurotransmitter functions occur possibly underlying the development of alcohol dependence. Therefore, modulators of these targets of ethanol can be useful pharmacotherapeutic agents in the treatment for alcohol dependence. The aim of this review is to summarize the patent background of these potential candidates clustering them according to their mechanism of effects.