Frontiers in CNS Drug Discovery

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 considerably 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.

Recent studies have indicated the significance of zinc in neurodegeneration after transient global ischemia. After ischemia, excess glutamate and zinc, which are released in the synaptic clefts, cause the apoptotic death of the target neurons, and finally lead the pathogenesis of vascular type of dementia. Considering the removal of zinc using zinc-sensitive chelators was effective in the prevention of neuronal death after transient global ischemia, it is highly possible that substances which protect against zinc-induced neuronal death will become a candidate for drugs of vascular type of dementia. Based on this ‘zinc hypothesis’, we have searched for such substances among various agricultural products including fruits, vegetables, and fishes using our developed in vitro screening system. Among tested, we found that carnosine (ß-alanyl histidine) protected against zinc-induced death of cultured neurons, and could get the patent as a drug of ischemia-induced neuronal death and the treatment/prevention for vascular type of dementia (patent No. 2007-314467) in Japan. Here, we review the perspective of protective substances of zinc-induced neuronal death as a drug of vascular type of dementia based on our studies and other numerous studies.

Among the molecular signaling pathways, protein kinase C (PKC) isozymes play a critical role in various types of learning and memory. Abnormal functions of PKC signal cascades in neurons have also been found to represent one of the earliest changes in the brains of patients with Alzheimer's disease (AD) and other types of memory deficits, including those related to cerebral ischemic/stroke events. In preclinical studies, an inhibition or impairment of PKC activity leads to compromised learning and memory, whereas an appropriate activation of PKC isozymes results in an enhancement of learning and memory and/or producing antidementic effects. PKC activators not only increase activity of PKC isozymes and thereby restore PKC signaling activity, including neurotrophic activity, synaptic/structural remodeling, and synaptogenesis in the hippocampus and related cortical areas, 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 cognition-enhancing agents and therapeutics against memory loss in the future.

Brain ischemia induces the IGF-1 system in damaged regions, and exogenous administration of IGF-1 after injury is neuroprotective and improves long-term neurological function. The short treatment window can be extended by mild hypothermia, probably due to delayed apoptosis. Nevertheless, the poor central uptake of IGF-1 and its mitogenic potential preclude clinical application.

The N-terminal tripeptide of IGF-1 (glycine-proline-glutamate, GPE) is neuroprotective after central administration. Central uptake of GPE is injury dependent, and it is rapidly degraded in the plasma. Intravenous infusion of GPE prevents brain injury and improves long-term functional recovery, with a broad effective dose range and a 3-7 hour therapeutic window. Its neuroprotective effects are also independent of cerebral reperfusion and not age selective. GPE does not interact with IGF receptors. G-2meth-PE, a GPE analogue with improved stability, has a prolonged plasma half life and is neuroprotective after ischemic injury. Neuroprotection by GPE and its analogue may involve modulating inflammation, promoting astrocytosis and inhibiting apoptosis and vascular remodeling

Cyclo-glycyl-proline (cGP) is an endogenous diketopiperazine possibly derived from GPE. Cyclic GP and its analogue cyclo-L-glycyl-L-2-allylproline (NNZ 2591) are neuroprotective after ischemic injury. NNZ 2591 crosses the BBB independent of injury and remains detectable several hours after a single administration. Repeated peripheral administration of NNZ 2591 improves somatosensorymotor function and long-term histological outcome.

Galantamine is a natural product that has attracted the interest of a number of researchers in a collaborative effort aimed at designing novel biologically active compounds for the treatment of Alzheimer's disease. In this article we review and update the syntheses of racemic and enantiomerically pure galantamine.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by deposition of extracellular amyloid plaques, formation of intracellular neurofibrillary tangles and neuronal dysfunction in the brain. A growing body of evidence indicates a central role for biometals such as copper in many critical aspects of AD. The amyloid beta (Aβ) peptide and its parental molecule, the amyloid precursor protein (APP) both modulate Cu and Zn metabolism in the brain. Therefore, aberrant changes to APP or Aβ metabolism could potentially alter biometal homoestasis in AD, leading to increased free radical production and neuronal oxidative stress. Modulation of metal bioavailability in the brain has been proposed as a potential therapeutic strategy for treatment of AD patients. The lipid permeable metal complexing agent, clioquinol (CQ), has shown promising results in animal models of AD and in small clinical trials involving AD patients. Moreover, a new generation of metal-ligand based therapeutics is currently under development. Patents now cover the generation of novel metal ligand structures designed to modulate metal binding to Aβ and quench metal-mediated free radical generation. However, the mechanism by which CQ and other metal complexing agents slow cognitive decline in AD animal models and patients is unknown. Increasing evidence suggests that ligandmediated redistribution of metals at a cellular level in the brain may be important. Further research will be necessary to fully understand the complex pathways associated with efficacious metal-based pharmaceuticals for treatment of AD.

Neurodegenerative disease broadly includes many different diseases, such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's, dementias with Lewy bodies, post-traumatic brain injury, and stroke. Although few common physiopathological changes have been discovered among these conditions, the semiology (if known), the triggered molecular pathways that lead to the observed pathologies, and the symptomatology are essentially different. These differences entail that the treatments, both current and future, have disease-specific indications. This idea led us to believe than it would be quite impossible to comprehensively review the progress made in drug discovery for all the neurodegenerative diseases and, therefore, we focused our attention in this review on the cutting-edge patents that pertain to the treatment of Alzheimer's disease (AD). Basic science discoveries have identified new targets/leads that have led the scientific community to develop new research initiatives in order to develop novel therapeutics entities and approaches. The purpose of this review is to discuss, through cutting-edge patents, the emergence of potential future treatments of AD. We hope to provide the reader with a broader and better understanding of what could be new therapies for AD during the next decade.

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 inhibition 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.

A compelling case for the potential utility of vasopressin (AVP) antagonists as a novel therapeutic class for the treatment of stress-related affective illness has emerged based on observations in depressed individuals, findings in animal models of anxiety and depression, and an understanding of changes in hypothalamic-pituitary-adrenal (HPA) axis regulation under chronic stress. The scientific bases for vasopressin antagonists as a pharmacotherapy for anxiety and depression include: 1) the neuroadaptation and dysregulation of HPA function that accompanies chronic stress in affected humans and in animal models of anxiety and depression, 2) recognition that AVP, not corticotrophin releasing factor (CRF), drives HPA function associated with chronic psychological stress, 3) the CNS localization of vasopressin V1a and V1b receptors in limbic system regions involved in HPA regulation and control of social behaviors, and 4) preclinical data showing efficacy in animal models employed as screens for anxiolytic and antidepressant activity.

The public health need for new pharmaceutical treatments for stress-related affective illness is well documented. In the United States alone, anxiety and depression affect some 35 million people each year and carry a conservatively estimated annual total economic burden of at least $125 billion. Existing pharmacotherapies for both indications are not uniformly effective and frequently have undesirable side effects. These limitations demonstrate that a new treatment approach through vasopressin receptor antagonism in the CNS may offer significant opportunities for improved outcomes. In this review, the development of compounds in this class since 2005 is considered. The most advanced clinical candidates and newer compounds described in recent patents are presented.

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 55 neurotransmitters, synonyms as well as compounds of recent known interest from May 2003 to July 2009. 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.

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. Data are based on experiments developed mainly with rodents; however, some updated research hypotheses that may well give some insights for the clinical sciences in men were also included.

Current epilepsy therapy is symptomatic using antiepileptic drugs. This therapy suppresses seizures but does not prevent or cure epilepsy. Treatment strategies that could interfere with the process leading to epilepsy (epileptogenesis) would have significant benefits over the current approach. Neuronal damage contributing to restructuralization of the neuronal networks (especially in the hippocampus during temporal lobe epilepsy) is one of the significant components of ongoing epileptogenesis. Thus, treatment strategies alleviating seizure induced neuronal damage may become significant players against the deteriorating process of epileptogenesis. Current antiepileptic drugs, especially valproic acid, have some neuroprotective potential. However, frequently this potential is either insufficient or the side effects of long-term therapy cancel out the benefits. The attention is therefore aimed at different classes of drugs with already established neuroprotective potential. Steroid hormones are under investigation, especially two groups of these compounds: β-estradiol and the selective estrogen receptor modulators – SERM. In low doses, β-estradiol has neuroprotective potency in neurodegenerative diseases. However, its use in seizure-induced neuroprotection is confounded by the common perception of proconvulsant features of estrogens. Here we review that these both proconvulsant and neuroprotective features apply only under specific conditions and may be separated by therapy taking into account the dosage paradigm, timing, sex of the subjects and their gonadal hormone status (including progesterone). Several studies have demonstrated that β-estradiol has indeed potency to protect neurons from seizure-induced damage. Additional studies are required to further elucidate the effects, exact conditions, and especially mechanisms of action of β-estradiol in seizure-induced neuroprotection since new specific SERM may help to avoid some undesirable effects.

The effect of dexamethasone (DEX) on brain excitability has been studied by using locomotor activity, straub reaction and epilepsy tests:

a. Morphine administration, (30-75-150 mg/kg,ip) induced a dose-related increase of the locomotor activity of mice, whereas DEX per se (0.1-1.0 – 10 mg/kg,ip) did not modify the activity of control mice. Pretreatment of mice with DEX 0.1 mg did not alter the hyperactivity produced by the three doses of morphine. In contrast, DEX administered at 1.0 mg reduced the morphine effects on locomotor activity, whereas DEX at 10 mg potentiated the morphine hypermotility.

b. Cocaine (10 mg/kg/i.p.) and amphetamine (5 mg/kg/i.p.) increased markedly locomotor activity of mice whereas DEX per se (0.1-1.0-10 mg/kg/i.p.) did not modify the activity of control mice. DEX pretreatment decreased the stimulating effects induced by cocaine and amphetamine. DEX pretreatment 0, 15, 30, 60 and 120 min before amphetamine or cocaine strongly decreased both amphetamine and cocaine effects, but no dose-related effect was observed. The time-course study performed with DEX revealed differences in its reducing effect on cocaine and amphetamine hypermotility when the groups of animals were treated with the steroid immediately before the cocaine (or amphetamine) injection when compared to those treated with the steroid later (15, 30, 60 and 120 min). Furthermore, actinomycin D was able to block the reducing effect of DEX on both amphetamine and cocaine hypermotility.

c. When morphine was administered in doses of 7.5, 15 and 30 mg/kg/i.p, a dose-dependent straub reaction was produced. DEX per se (0.1-1.0-10 mg /kg,i.p.) did not modify the tail of control mice. Pre-treatment with DEX 120 min before morphine injection caused a dose-dependent reduction of straub reaction. Cycloheximide (15 mg/kg,i.p.) administered 2h before morphine did not change morphine-induced straub reaction, but was able to prevent the effects of DEX on morphine-induced straub reaction. The glucocorticoid receptor antagonist RU-38486 (15 mg/kg,i.p.) did not affect morphine-induced straub reaction, whereas it was able to block the effects of dexamethasone on morphine-induced straub reaction.

d. The inhibitory effects exerted by DEX on the epileptiform activity induced by morphine were investigated in two different experimental modeis with two different animal species. In the first series of experiments, DEX administered i.v. in rabbits 30 min before i.c.v. administration of morphine completely prevented both epileptiform and background EEG as well as behavioral alterations induced by morphine. Cycloheximide (a protein synthesis inhibitor) pretreatment reversed the antagonistic effect induced by DEX on the behavioral and EEG alterations induced by morphine. In the second series of experiments, the effects exerted by DEX were investigated on morphineinduced CA1 epileptiform bursting on rat hippocampal slices in vitro. DEX pretreatment 10 to 60 min before morphine strongly prevented the morphine effects in a concentration- and time-dependent manner. Sixty min of DEX pretreatment also prevented the epileptiform bursting induced by the selective µ optate receptor agonist DAMGO, whereas it did not significantly affect the increase of the CA1 population spike amplitude due to the selective d opiate receptor agonist DPDPE. The addition of cycloheximide to the slice-perfusing medium containing DEX prevented the inhibitory effects of the drug toward the morphine and DAMGO-induced CA1 epileptiform bursting. Our results indicate that DEX induces an inhibition on the epileptiform activity induced by morphine and DAMGO. The time lag (30-60 min) which is necessary for revealing the inhibitory influence of DEX on opiate epileptiform activity induced both in vivo and in vitro, and the inhibitory effect exerted by cycloheximide on DEX activity strongly support the hypothesis of a genomic corticosteroid effect within the central nervous system.

e. The effects of DEX and RU-38486 plus DEX on the neocortical spikeand- wave spindling episodes (S) in the ECoG of DBA/2J mice was also investigated.

DEX (1-10-100 μg/kg/i.p.) dose-dependently reduce the S of DBA/2J mice. This effect appears 30 min after drugs administration and lasts for the duration of the recording period (240 min). RU-38486, a glucocorticoid receptor antagonist, (1-10-100 μg/kg/i.p.) injected two hours before DEX, was able to block totally the steroid effect.

These results further indicate that DEX induces significant reduction on S of DBA/2J mice confirming the ability of DEX to control brain excitability.

Our results suggest that DEX plays an important regulatory role on the brain excitability. The ability of actinomicyn D and/or cycloheximide as well as of RU- 38486 to block DEX's effects indicates that the steroid acts through the involvement of a protein-synthesis-dependent mechanism via glucocorticoid receptors.

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.

Adenosine A2A receptors are highly concentrated in the striatum, where they play an important modulatory role of glutamatergic transmission to the GABAergic enkephalinergic neuron, whose function is particularly compromised in Parkinson's disease and in the early stages of Huntington's disease. An important amount of preclinical data suggested the possible application of A2A receptor antagonists in Parkinson's disease, particularly as adjuvant therapy to the currently used dopaminergic agonists. Several A2A receptor antagonists are currently in clinical trials in patients with Parkinson's disease and initial results have been promising. In recent years, many pharmaceutical companies have started programs to develop A2A antagonists for Parkinson's disease and for other indications, such as neurodegenerative diseases in general, depression, and restless legs syndrome. Antagonists with high A2A receptor affinity and selectivity have been developed from various chemical classes of compounds, including xanthines, adenines and other amino-substituted heterocyclic compounds. Novel structures include benzothiazole and thiazolopyridine derivatives. The present review describes properties of standard A2A receptor antagonists including those in clinical development. Furthermore, the different chemical classes of A2A receptor antagonists that have been described in the literature, including recent patent literature, will be presented.

p>Major efforts have gone into developing ‘benzodiazepine-like’ drugs that are more selective than benzodiazepines in therapeutic effects (e.g., anxiolytic versus hypnotic) or lack the adverse effects of benzodiazepines. More targetspecific benzodiazepine-like drugs are thought to act selectively on neuronal benzodiazepine receptors versus astrocytic mitochondrial benzodiazepine receptors (re-named translocator protein [18 kDa]) and/or on GABAA/benzodiazepine receptor complexes displaying specific subunits. It is overlooked that astrocytes also express membrane-associated GABAA-like receptors that are inhibited both by the ‘peripheral-type’ benzodiazepine antagonist PK11195 and the ‘neuronal’ antagonist flumazenil, and because of a high intracellular Cl- concentration are depolarizing and enhance Ca2+ entry through L-channels. Functional effects of depolarization-mediated Ca2+ uptake in astrocytes (stimulation of glycogenolysis, gap junction-mediated connectivity and Na+, K+, 2Cl- co-accumulation) suggest that activation of this receptor is functionally relevant, but because of its unknown therapeutic actions(s) we named it the Joker receptor. Based on observations by Cahoy et al. [1] that astrocytes account for 70% of GABAA receptor subunits α2 and β1 and > 90% of subunit γ1, and evidence that stimulation of α2 and γ1 subunits induces anxiolysis, we present evidence that drugs acting on the Joker receptor are anxiolytic, without sedative effects and with little abuse potential.

The presence and function of muscarinic receptor subtypes both in neuronal and non-neuronal cells have been demonstrated using extensive pharmacological data emerging from studies on transgenic mice. Acetylcholine, in fact is synthesized not only in the nervous system but also in other tissues where its local action contributes to the modulation of various cell functions (e.g. survival, proliferation). The possible involvement of acetylcholine and muscarinic receptors in different pathologies has been proposed in recent years and is becoming an important area of study. Although the lack of selective muscarinic receptor ligands has for a long time limited the definition of therapeutic treatment based on muscarinic receptors as targets, some muscarinic ligands such as cevimeline (patents US4855290; US5571918) or xanomeline (patent , US5980933) have been developed and used in pre-clinical or in clinical studies for the treatment of nervous system diseases (Alzheimer and Sjogren's diseases).

This review will be focused on the potential implications of muscarinic receptors in the pain therapy and in different pathologies including tumors. Moreover the future use of muscarinic ligands in therapeutic protocols in cancer therapy will be discussed, considering that some muscarinic antagonists currently used in the treatment of genitourinary disease (e.g. darifenacin,; patent, US5096890; US6106864) have also been demonstrated to arrest tumor progression in nude mice.

The involvement of muscarinic receptors in nociception has also been reported. In fact muscarinic agonists such as vedaclidine, CMI-936 and CMI-1145 have been demonstrated to have analgesic effects, in animal models comparable or more pronounced to those produced by morphine or opiates.

The neurokinin (NK) receptor family has been proposed as targets for neural-related diseases. The experimental studies indicate that this family of receptors might also be targets for malignancies, both solid and hematological tumors. However, an understanding of the biology of other molecules with sequence similarity to NK receptors is required. Of significance is the HGFIN gene that shares structural homology with NK1. Through this homology, the HGFIN interacts with the high affinity ligand of NK1, substance P. This report discusses potential applications for targets against NK receptors, and the role of HGFIN in drug designs. This review is relevant for central and peripheral nervous system drug development, and also cancer drugs for breast and neuroblastoma. The potential for leukemia drugs and Patents is also discussed.

Gastrin-releasing peptide (GRP) is a mammalian counterpart of the amphibian peptide bombesin (BB) that stimulates cell proliferation, acts as a growth factor in the pathogenesis of many types of cancer, and regulates several aspects of neuroendocrine function. BB and GRP act by binding to the GRPpreferring type of BB receptor (GRPR, also known as BB2 receptor), a member of the superfamily of G-protein coupled membrane receptors. This review summarizes recent evidence from animal and human studies indicating that abnormalities in GRPR function in the brain might play a role in the pathogenesis of neurological and psychiatric disorders, and suggesting that BB, GRP, and GRPR antagonists might display therapeutic actions in central nervous system diseases.

G protein-coupled receptors (GPCRs) comprise the largest family in the receptorome (the subset of the genome encoding membrane receptors). These signal transducing molecules convey extracellular signals into the cell interior by activating intracellular networks such as heterotrimeric G protein-dependent signaling pathways. They are widely distributed in the nervous system where they mediate a myriad of key processes including cognition, mood, appetite, pain and synaptic transmission. Currently, at least 30% of marketed drugs are GPCR modulators. With global aging, the CNS drug market is set to grow. GPCR ligands for CNS receptors feature prominently in the pipeline of major pharmaceutical companies. Among GPCRs widely investigated as drug targets include the metabotropic glutamate, adenosine and cannabinoid receptors, as evidenced by recently patented ligands for these receptors. Metabotropic glutamate receptors regulate signaling by glutamate, the major excitatory brain neurotransmitter, while adenosine is a ubiquitous neuromodulater mediating diverse physiological effects. Recent patents for ligands of these receptors include mGluR5 antagonists and adenosine A1 receptor agonists. Cannabinoid receptors used to be one of the most important GPCR drug discovery targets for treating obesity and metabolic syndrome, but the unexpected withdrawal of several CB1 antagonists/inverse agonists has prompted alternative approaches. These recent patents are the outcome of the continuing focus of many pharmaceutical companies to identify novel GPCR agonist, antagonist or allosteric modulators useful to treat psychiatric and neurological diseases for which more effective drugs are urgently needed.

The synaptic transmission and, consequently, the 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 affecting the CNS, have traditionally been classified as agonists or antagonists by the pharmacologist. 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.

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.

The effect of dexamethasone (DEX) and its interaction with morphine has been studied on transmurally-stimulated guinea-pig ileum preparation, gastrointestinal transit, analgesia, withdrawal and hypotension.

Transmurally-stimulated guinea-pig ileum preparation: DEX dose-dependently reduced the contractions of the ileum. Proteic synthesis inhibitors did not modify the inhibition induced by DEX whereas RU-38486, a glucocorticoid antagonist receptor, antagonized completely the inhibitory effect of DEX.

Gastrointestinal transit: DEX was found to antagonize morphine-, atropine- and verapamil-induced constipation. Cycloheximide does not modify the DEX effects. RU-38486 reverses both the inhibitory action of DEX on gastrointestinal transit and its reducing effect on morphine-induced constipation.

Analgesia: DEX reduced the antinociception induced by mu agonists, morphine, DAMGO and beta endorphin whereas the steroid exerted little or no influence on the antinociception induced by a delta1 agonist, DPDPE and delta2 agonist deltorphin II. DEX potentiated the antinociception induced by the K agonist, U50,488.

Cycloheximide, a protein synthesis inhibitor, prevented the antagonism by DEX of responses to the mu opioid agonists. Finally, i.c.v. injection of DEX significantly reduced morphine analgesia in Swiss mice whereas no effects were observed in DBA/2J and C57BL/6 mice. In addition, i.p. injection of DEX significantly reduced morphine analgesia in all three strains.

Withdrawal: DEX treatment before or after the opioid agonists tested was capable of both preventing and reverting the naloxone-induced contracture after exposure to µ opiate agonists morphine and DAGO in a concentration- and time-dependent fashion. Also, the steroid reduced naloxone-induced contracture following the exposure to U50-488H only when injected before the k opiate agonist. Finally, it did not affect the naloxone-contracture after exposure to deltorphin.

Pretreatment with RU-38486, a glucocorticoid receptor antagonist, inhibited DEX antagonism on responses to both µ and k agonists whereas pretreatment with cycloheximide, a protein synthesis inhibitor, blocked only the antagonistic effects of dexamethasone on responses to the µ opioid agonists.

The addition to the organ bath of a neutralizing anti-lipocortin-1 antibody, at a dilution of 1:10.000, prior to DEX addition, reverted the inhibitory effect of the steroid. Furthermore, a polyclonal anti-type II extracellular phospholipase A2 antibody, in a dilution 1:1000, mimicked DEX inhibitory effect.

Hypotension: DEX per se at a dose of 7.5 µmol/kg, i.v. did not significantly modify the mean arterial blood pressure of animals. DEX administration 90 min, but not 30 or 60 min, before the opioid agonists injection, prevented the hypotension induced by morphine or U50-488H, but not that induced by DAGO or deltorphin II. Pretreatment with RU-38486 (mifepristone; 7.5 μmol/kg, i.v.), a glucocorticoid receptor antagonist, 15 min before the steroid, prevented DEX inhibition of hypotension induced by morphine and U50-488H. Furthermore, pretreatment with cycloheximide, a protein synthesis inhibitor (3.5 μmol/kg, i.v.), was also able to abolish the effects of DEX on morphine- and U50-488H-induced hypotension. Our data indicate that in the both in vivo and in vitro models there is an important functional interaction between the corticosteroid and the opioid systems at least at the mu. receptor level, while delta and K receptors are modulated in different ways. These results strongly confirm a functionalinteraction between DEX and opiods system.

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).

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.

Obesity is considered as one of the risk factors for metabolic disorders. There is an increasing evidence that obesity is under control of several cytokines and hormone in the brain. Brain histamine and H3 receptors are important factors for regulating obesity. The results of physiological and pharmacological studies revealed that brain histamine and H3 receptors are involved in the regulation of obesity. In this review, we describe the implication and patent for developing H3 receptor antagonists and their therapeutic potential of obesity.

Alcohol use disorders represent an extensive public health problem all over the world affecting approximately 2 billion alcohol users, causing 1.8 million deaths (3.2% of total) and 58.3 million (4% of total) of Disability-Adjusted Life Years (DALYs) worldwide as reported by the WHO lately. 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 effects 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 seducing 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 chapter is to summarize the recent patent background of these potential candidates clustering them according to their mechanism of effects.

Melatonin, the pineal gland hormone, is widely distributed in mammalian tissues and exerts its action via two melatonin receptor sub-types, MT1 and MT2. Melatonin is known to play functional roles in regulating circadian rhythms and seasonal reproduction. In recent years, growing evidence has also linked melatonin to a variety of other body systems and disease states, thus highlighting its significance as a therapeutic agent. However, due to its properties, melatonin is ineffective in clinical use, thus prompting the development of melatoninergic ligands that mimic the actions of melatonin but in a manner that is more potent and specific for melatonin receptors. An additional focus has been to develop ligands that exhibit receptor subtype selectivity. While there are over seventy patents on melatoninergic ligands, success in developing therapeutically effective melatoninergic ligands has been varied. However, the recent approval of Ramelteon for treatment of sleep disorders and the evaluation of other compounds in clinical trials have highlighted their clinical importance. In this review an overview of recently developed novel melatoninergic ligands is provided including recently filed patents and compounds undergoing clinical evaluation.

A number of Voltage-Gated Sodium Channels (VGSC) are 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+/Ca2+ exchanger resulting in reduced intracellular Ca2+ levels during lymphocyte activation. Furthermore, in Jurkat cell line VGSC appear to be involved in cell volume regulation, migration in an 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 suggests that the testing of newly patented VGSC blockers for their effect on immunity may be worthwhile.

Clinical trials and clinical studies, using patented drugs and drugs off patent, provide data that impact the best treatment practices for substance abuse and dependence. In the United States, medications have been approved for use in the treatment of both alcohol and opioid dependence. Medications used in the detoxification from drug abuse and dependence provide symptomatic relief of drug and alcohol withdrawal. For long term treatment or medical maintenance treatment, medications eliminate the physiological effects of drug use by blocking drug-receptor binding in the brain. Patented drugs remain an important source of candidate pharmacotherapies comprising medication assistant treatment, part of a comprehensive treatment plan for drug dependence that addresses the medical, social, and psychological needs of the patient. Therefore, patented drugs characterized by demonstrable interactions with neurotransmitters in the brain, are attractive candidates for treatment efficacy trials. An effective long term treatment paradigm for reducing drug dependence is the concomitant use of medications that block the effects of drug use with behavior change counseling and psychotherapy. Medications which have demonstrated effectiveness for the long term treatment of opioid dependence are methadone, buprenorphine, and naltrexone. Pharmacotherapies used in the treatment of alcohol dependence include acamprosate, antabuse and naltrexone.

A reliable indicator for successful treatment of drug dependence is time in treatment. Patients remain in treatment for longer periods of time when they perceive that their health care environment is supportive and non-stigmatizing, with a good patient-provider relationship, and where they feel that their needs are identified and met. Additional medications may be needed for individual comprehensive substance abuse treatment plans, particularly for individuals who abuse stimulants or have co-occurring mental health disorders. Adapting a comprehensive drug treatment paradigm globally requires identifying and testing new drug candidates while building and changing programs to become more patient centered, adapting to local socio-cultural conditions to promote access to care and treatment and integrating medical, psychological, and social services.