Recent Patents on CNS Drug Discovery (Discontinued) - Volume 3, Issue 1, 2008

The neurokinin-3 (NK3) is one of the tachykinin peptide neurotransmitter / neuromodulator receptor family. NK3 receptors are predominantly expressed in neurons of both the peripheral and central nervous systems and in particular, in many of the forebrain areas, such as frontal, parietal and cingulate cortices, and basal ganglia structures implicated in psychiatric disease states. Consistent with this localization pattern, NK3 receptors appear to modulate monoaminergic and amino acid neurotransmission within these structures. Taken together these observations have lead to the speculation that modulators of NK3 receptor activity may have therapeutic utility in psychiatric diseases such as schizophrenia and affective disorders. This speculation has recently gained clinical credence through a number of reports of efficacy in placebo controlled studies. In this article, the authors review the recent patent literature highlighting the various NK3 receptor modulation strategies for potential therapeutic utility in psychiatric disease indications.

Autoimmune encephalitis is a heterogeneous group of disorders probably resulting from a reaction of the immune system against antigens of the central nervous system. Historically, the autoimmune hypothesis was based on the neuropathological discovery of an immune cellular infiltrate in the brain parenchyma and around the cerebral blood vessels, resembling a form of viral encephalitis without any detectable viral antigens. These syndromes can be divided into forms with prevalent grey matter involvement, forms with prevalent white matter damage and forms in which the target of the immune process is the vessels. In this paper, we review recent knowledge about the syndromes belonging to the first group. This group encompasses syndromes in which there is neuronal loss and antibodies directed against antigens expressed in the neurons (anti-neuronal antibodies) are frequently detected in the sera or cerebrospinal fluid. These antibodies are not necessarily the cause of neurological impairment but are important markers for these syndromes. It is essential to acquire knowledge on these disorders since they are an important cause of rapidly progressive cognitive decline and behavioural problems which may remain underrecognized, but often improve with immunomodulatory therapies.

Human immunodeficiency virus (HIV-1) is the responsible agent of acquired immunodeficiency syndrome (AIDS), a multi system disorder including the central nervous system (CNS). The CNS is an immunological privileged site providing a sanctuary and reservoir for HIV-1. Monocytes derived macrophages (MDM) and microglia play a critical role in the development of HIV-associated dementia (HAD). Although the use of highly active antiretroviral therapy (HAART) has led to a strong reduction of HAD incidence, the prevalence of minor HIV-1 associated cognitive impairment appears rising among AIDS patients. Various factors including toxicity, insurgence of drug resistance and sometimes limited access to HAART, contribute to this phenomenon. Independent evolution of drug resistance mutations in several areas of the CNS may emerge as consequence of incomplete suppression of HIV-1, probably related to poor penetration of antiretroviral drugs into CNS. The emergence of resistant virus in the CNS may considerable influence the outcome of neurological disease and also the reseeding of HIV-1 in the systemic circulation upon failure of therapy. In this review, we outline the current state of knowledge regarding the pathophysiology of CNS injury in HIV-1 infection and will focus on the effects of HAART on CNS.

Multiple sclerosis (MS) is a demyelinating disease in which myelin autoreactive T cells drive a chronic inflammatory process leading to myelin destruction. A sexual dimorphism has been described, with prevalence in females and a better clinical course during pregnancy. Specific receptors have been identified for sex steroids in the cytoplasm of immune and neural cells. Experimental autoimmune encephalomyelitis (EAE), the most frequently studied animal model for MS, showed sex differences in the disease course and improvement by the use of exogenous sex steroids. The recent pilot studies in vivo also reported an improvement of MS by the administration of gonadal hormones (replacement therapy, testosterone, estriol) in the short time. A patent proposed estriol therapy to treat autoimmune related disorders (including MS). A clinical European trial is ongoing on the use of nomegestrol/estradiol in the post-partum period in order to prevent the relapses. Integrated therapies appear to be effective in both male and female MS patients.

Aggression is conceived as a social behavior that, in conjunct with motor and visceral displays, is related with acts for obtaining a specific goal or is directed against threatening stimuli with the intention of causing harm, either for attack or defense. Here it is reviewed basic concepts and aspects for the classification of aggression, the behavioral displays regarded as aggressive in animal models, the basic neural circuits that are involved to them and the pharmacological approaches involving some neurotransmitters (5-HT, dopamine and GABA) and drugs that can be used to identify the neural basis of aggression and to modulate its expression. Drug patents are referred in the text. Data are based on experiments developed mainly with rodents; however, some research hypotheses that may well give some insights for the clinical sciences in men were also included.

Since the introduction of levodopa therapy in the 60's, there has yet to be a more efficacious drug identified for the symptomatic treatment of Parkinson's disease (PD). Perhaps more importantly, there has been little to no success finding agents that have proven effective in protecting against neurodegeneration. In fact, recent development efforts have been primarily directed at stabilizing the side effects (wearing off, drug-induced dyskinesias, motor fluctuations) that accompany prolonged levodopa therapy, such as catechol O-methyltransferase inhibiton to combat the side effects of levodopa therapy. This review also examines alternative strategies to levodopa therapy, including potential adjuncts therapies, recent patents and future directions to be evaluated for neuroprotection. While dopamine agonists are inferior to levodopa in controlling motor symptoms, potential benefits and drawbacks with this class of drugs are presented. Potential neuroprotective agents such as monoamine oxidase-B inhibitors are also examined for their therapeutic benefit as well as their potential to slow disease progression. Neuroprotection will continue to be an important area of research in CNS drug development.

Zolpidem is a selective agonist of the benzodiazepine subtype receptor BZ1. The highest density of this receptor is in the output structures of the basal ganglia. The basal ganglia are pathologically involved in many movements disorders. Thus, zolpidem has accumulated attention for a possible drug to treat neurological signs and symptoms in Parkinsonian diseases. In this mini-review, I reviewed effects of zolpidem as movement disorders including Parkinson's disease, progressive supranuclear palsy, dystonia and so on. In addition, I reviewed a possible mechanism of zolpidem for movement disorders.

Aging is characterized by a progressive deterioration of physiological functions and metabolic processes. Healthy aging remains one of the ideals of modern society. In aging and in diseases associated with the elderly, such as Alzheimer's or Parkinson's, the loss of cells in vital structures or organs may be related to several factors, among which the production of reactive oxygen species (ROS) by mitochondria is a common denominator, one that leads to DNA damage, apoptosis and death. Although a diet rich in antioxidants seems to offer hope in delaying the onset of unhealthy disorders that accompany aging, no clinical treatment as such has yet been developed and anti-aging drugs are still unavailable. It is well established that reducing food intake (caloric restriction) extends the life-span in a wide range of species. The protein implicated in this protective process is the silent information regulator 2 (SIR2, SIRT1 in mammals), an enzyme that belongs to a nicotinamide adenine dinucleotide (NAD)+-dependent protein deacetylases. SIRs regulate gene silencing, DNA repair, rDNA recombination, and ageing, apart from regulating programmed cell death. In this context, increasing SIRT1 has been found to protect cells against amyloid-beta-induced ROS production and DNA damage, thereby reducing apoptotic death in vitro. Moreover, it has been demonstrated that Alzheimer's and Huntington's disease neurons are rescued by the over-expression of SIRT1, induced by either caloric restriction or administration of resveratrol, a potential activator of this enzyme. The therapeutic use of resveratrol (a polyphenol present in red wines) and other related compounds, which utilize SIRT1 pathway modulators, in treating aging-related brain disorders will be discussed in this review. Provided herein are novel new compound related with resveratrol or sirtinol that are able to modulate sirtuin activity that will be tested to treat and/or prevent a wide variety of diseases including, disorders related to aging or neurodegenerative diseases,

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