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Pharmacological Target (pharmacological + target)
Kinds of Pharmacological Target Selected AbstractsAMP-activated protein kinase: role in metabolism and therapeutic implicationsDIABETES OBESITY & METABOLISM, Issue 6 2006Greg Schimmack AMP-activated protein kinase (AMPK) is an enzyme that works as a fuel gauge which becomes activated in situations of energy consumption. AMPK functions to restore cellular ATP levels by modifying diverse metabolic and cellular pathways. In the skeletal muscle, AMPK is activated during exercise and is involved in contraction-stimulated glucose transport and fatty acid oxidation. In the heart, AMPK activity increases during ischaemia and functions to sustain ATP, cardiac function and myocardial viability. In the liver, AMPK inhibits the production of glucose, cholesterol and triglycerides and stimulates fatty acid oxidation. Recent studies have shown that AMPK is involved in the mechanism of action of metformin and thiazolidinediones, and the adipocytokines leptin and adiponectin. These data, along with evidence that pharmacological activation of AMPK in vivo improves blood glucose homeostasis, cholesterol concentrations and blood pressure in insulin-resistant rodents, make this enzyme an attractive pharmacological target for the treatment of type 2 diabetes, ischaemic heart disease and other metabolic diseases. [source] Synthesis of Polyamines from Ethylenediamine and Their Platinum(II) Complexes, Potential Antitumor AgentsEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 9 2006Mara Rubia Costa Couri Abstract This work describes the synthesis and characterization of five new amine ligands and also the preparation and characterization of their respective platinum(II) complexes by reaction with K2PtCl4 in water. These ligands were obtained by treatment of different halides or epoxides with ethylenediamine. Cytotoxic activity and cellular accumulation of three complexes were investigated in a human small-cell lung carcinoma cell line and its cisplatin resistant subline. The introduction of a spacer (cycle) between the two platinum atoms leads to a significant decrease in cytotoxic activity. At equitoxic doses, the intracellular platinum concentrations found for compounds 12 and 15 were significantly higher than those found for the reference compounds, cisplatin, carboplatin, or compound 9. This fact suggests that the formation of adducts between compounds 12 and 15 and the putative pharmacological target, DNA, is less favored. If these compounds bind more slowly to DNA, interaction with other intracellular ligands such as sulfur-containing molecules will become relevant and it may be the reason for the elevated intracellular platinum concentrations. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006) [source] Mapping of the active site of glutamate carboxypeptidase II by site-directed mutagenesisFEBS JOURNAL, Issue 18 2007Petra Ml, ochová Human glutamate carboxypeptidase II [GCPII (EC 3.4.17.21)] is recognized as a promising pharmacological target for the treatment and imaging of various pathologies, including neurological disorders and prostate cancer. Recently reported crystal structures of GCPII provide structural insight into the organization of the substrate binding cavity and highlight residues implicated in substrate/inhibitor binding in the S1, site of the enzyme. To complement and extend the structural studies, we constructed a model of GCPII in complex with its substrate, N -acetyl- l -aspartyl- l -glutamate, which enabled us to predict additional amino acid residues interacting with the bound substrate, and used site-directed mutagenesis to assess the contribution of individual residues for substrate/inhibitor binding and enzymatic activity of GCPII. We prepared and characterized 12 GCPII mutants targeting the amino acids in the vicinity of substrate/inhibitor binding pockets. The experimental results, together with the molecular modeling, suggest that the amino acid residues delineating the S1, pocket of the enzyme (namely Arg210) contribute primarily to the high affinity binding of GCPII substrates/inhibitors, whereas the residues forming the S1 pocket might be more important for the ,fine-tuning' of GCPII substrate specificity. [source] Contribution of endothelium-derived hyperpolarizing factors to the regulation of vascular tone in humansFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2008Jeremy Bellien Abstract Endothelium plays a crucial role in the regulation of cardiovascular homeostasis through the release of vasoactive factors. Besides nitric oxide (NO) and prostacyclin, increasing evidences show that endothelium-derived hyperpolarizing factors (EDHF) participate in the control of vasomotor tone through the activation of calcium-activated potassium channels. In humans, the role of EDHF has been demonstrated in various vascular beds including coronary, peripheral, skin and venous vessels. The mechanisms of EDHF-type relaxations identified in humans involved the release by the endothelium of hydrogen peroxide, epoxyeicosatrienoic acids (EETs), potassium ions and electronical communication through the gap junctions. The role of EETs could be particularly important because, in addition contributing to the maintenance of the basal tone and endothelium-dependent dilation of conduit arteries, these factors share many vascular protective properties of NO. The alteration of which might be involved in the physiopathology of cardiovascular diseases. The evolution of EDHF availability in human pathology is currently under investigation with some results demonstrating an increase in EDHF release to compensate the loss of NO synthesis and to maintain the endothelial vasomotor function whereas others reported a parallel decrease in NO and EDHF-mediated relaxations. Thus, the modulation of EDHF activity emerges as a new pharmacological target and some existing therapies in particular those affecting the renin,angiotensin system have already been shown to improve endothelial function through hyperpolarizing mechanisms. In this context, the development of new specific pharmacological agents especially those increasing EETs availability may help to prevent endothelial dysfunction and therefore enhance cardiovascular protection in patients. [source] Systemic Administration of Arecoline Reduces Ethanol-Induced Sleeping Through Activation of Central Muscarinic Receptor in MiceALCOHOLISM, Issue 1 2010Yan-Ping Sun Background:, Epidemiological evidence of co-use of alcohol and areca nuts suggests a potential central interaction between arecoline, a major alkaloid of areca and a muscarinic receptor agonist, and ethanol. Moreover, the central cholinergic system plays an important role in the depressant action of ethanol and barbiturates. The purpose of this study was to investigate the effects of arecoline on pentobarbital- and ethanol-induced hypnosis in mice. Methods:, Male ICR mice were tested for locomotor activity following acute systemic administration of ethanol alone, arecoline alone, or ethanol plus arecoline. For the loss of the righting reflex (LORR) induced by pentobarbital and ethanol, sleep latency and sleeping duration were evaluated in mice treated with arecoline alone or the combination of arecoline and scopolamine or methscopolamine. Results:, Ethanol (1.0 to 3.0 g/kg, i.p.) reduced locomotor activity significantly and a declining trend was observed after treatment with arecoline (0.25 to 1.0 mg/kg, i.p.), but there were no synergistic effects of ethanol and arecoline on locomotor activity. The experiments on LORR demonstrated that arecoline (0.125 to 1.0 mg/kg, s.c.) shortened the duration of sleeping induced by ethanol (4.0 g/kg, i.p.), but not pentobarbital (45 mg/kg, i.p.). In addition, alterations of sleep latency were not obvious in both pentobarbital- and ethanol-induced LORR. Statistical analyses revealed that scopolamine (centrally acting), but not methscopolamine (peripherally acting), could antagonize the effect of arecoline on the duration of ethanol-induced LORR in mice. Conclusions:, These results suggest that central muscarinic receptor is a pharmacological target for the action of arecoline to modulate ethanol-induced hypnosis. [source] Cloning and pharmacological characterization of the equine adenosine A2A receptor: a potential therapeutic target for the treatment of equine endotoxemiaJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2006C. I. BRANDON The aim of the current study was to clone the equine adenosine A2A receptor gene and to establish a heterologous expression system to ascertain its pharmacologic profile via radioligand binding and functional assays. An eA2A -R expression construct was generated by ligation of the eA2A cDNA into the pcDNA3.1 expression vector, and stably transfected into human embryonic kidney cells (HEK). Binding assays identified those clones expressing the eA2A -R, and equilibrium saturation isotherm experiments were utilized to determine dissociation constants (KD), and receptor densities (Bmax) of selected clones. Equilibrium competition binding revealed a rank order of agonist potency of ATL > CV-1808 > NECA > 2-CADO > CGS21680, and a rank order of antagonist potency as ZM241385 > 8-phenyltheophylline > p -sulfophenyltheophylline > caffeine. Furthermore, adenylate cyclase assays using selective A2A -R agonists revealed that the eA2A -R functionally coupled to G,s as indicated by an increase in intracellular [3H]cAMP upon receptor activation. Finally, NF- ,B reporter gene assays revealed a CGS21680 concentration-dependent inhibition of NF- ,B activity. These results indicate that the heterologously expressed eA2A -R has a pharmacological profile similar to that of other mammalian A2A receptors and thus can be utilized for further characterization of the eA2A -R to ascertain whether it can serve as a suitable pharmacological target for equine inflammatory disease. [source] The effect of sevoflurane on glutamate release and uptake in rat cerebrocortical presynaptic terminalsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 1 2002M. L. Vinje Background: Volatile anaesthetics exert their effect in the brain mainly by reducing synaptic excitability. Isoflurane abates excitation by reducing the release and increasing the uptake of transmitter glutamate into the presynaptic terminal. The exact molecular mechanisms exerting these effects, however, are not clear. Voltage-gated calcium channels have been proposed as the pharmacological target. The present study examines the effect of sevoflurane on synaptic glutamate release and free cytosolic calcium and the effect on high- and low-affinity uptake of L-glutamate using isolated presynaptic terminals prepared from rat cerebral cortex. Methods: Released glutamate was measured fluorometrically in a spectrophotometer as the fluorescence of NADPH and calcium as the fluorescence of fura-2. 4-aminopyridine was used to induce membrane depolarization. Glutamate uptake was measured in a series of different concentrations of L-glutamate corresponding to the high- and the low- affinity uptake systems adding a fixed concentration og radiolabelled glutamate. The labelling was measured by counting disintegrations per min in a ,-scintillation counter. Results: Sevoflurane reduced the calcium-dependent glutamate release in a dose-dependent manner as sevoflurane 1.5, 2.5 and 4.0% reduced the release by 58, 69 and 94%, respectively (P<0.05). Membrane depolarization induced an increase in free cytosolic calcium by 25%. Sevoflurane did not affect this increase. Neither the high- nor the low-affinity uptake transporter systems are affected by the anaesthetic. Conclusion: These results indicate that different volatile anaesthetics may act differently on the presynaptic terminal. The exact modes of action have to be further investigated. [source] Recent advances in the neurobiology of anxiety disorders: Implications for novel therapeutics,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 2 2008Sanjay J. Mathew Abstract Anxiety disorders are a highly prevalent and disabling class of psychiatric disorders. This review focuses on new directions in neurobiological research and implications for the development of novel psychopharmacological treatments. Neuroanatomical and neuroimaging research in anxiety disorders has centered on the role of the amygdala, reciprocal connections between the amygdala and the prefrontal cortex, and, most recently, alterations in interoceptive processing by the anterior insula. Anxiety disorders are characterized by alterations in a diverse range of neurochemical systems, suggesting ample novel targets for drug therapies. Corticotropin-releasing factor (CRF) concentrations are elevated in a subset of anxiety disorders, which suggests the potential utility of CRF receptor antagonists. Pharmacological blockade of the memory-enhancing effects of stress hormones such as glucocorticoids and noradrenaline holds promise as a preventative approach for trauma-related anxiety. The glutamatergic system has been largely overlooked as a potential pharmacological target, although convergent preclinical, neuroimaging, and early clinical findings suggest that glutamate receptor antagonists may have potent anxiolytic effects. Glutamatergic receptor agonists (e.g., D -cycloserine) also have an emerging role in the treatment of anxiety as facilitators of fear extinction during concurrent behavioral interventions. The neuropeptides substance P, neuropeptide Y, oxytocin, orexin, and galanin are each implicated in anxiety pathways, and neuropeptide analogs or antagonists show early promise as anxiolytics in preclinical and/or clinical research. Each of these active areas of research holds promise for expanding and improving evidence-based treatment options for individuals suffering with clinical anxiety. © 2008 Wiley-Liss, Inc. [source] Chronic Administration of Ketamine Elicits Antidepressant-Like Effects in Rats without Affecting Hippocampal Brain-Derived Neurotrophic Factor Protein LevelsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2008Lêda S. Garcia The present study was aimed to evaluate behavioural and molecular effects of the chronic treatment with ketamine and imipramine in rats. To this aim, rats were 14 days treated once a day with ketamine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and then subjected to the forced swimming and open-field tests. Ketamine and imipramine, at the all doses tested, reduced immobility time, and increased both climbing and swimming time of rats compared to the saline group, without affecting spontaneous locomotor activity. Brain-derived neurotrophic factor (BDNF) hippocampal levels were assessed in imipramine- and ketamine-treated rats by ELISA sandwich assay. Chronic administration of both drugs, ketamine and imipramine, did not modify BDNF protein levels in the rat hippocampus. In conclusion, our findings demonstrate for the first time that chronic administration of acute inactive doses of ketamine (5 mg/kg) becomes active after chronic treatment, while no signs of tolerance to the behavioural effects of ketamine were observed after chronic administration of acute active doses (10 and 15 mg/kg). Finally, these findings further support the hypothesis that NMDA receptor could be a new pharmacological target for the treatment of mood disorders. [source] PTEN: a promising pharmacological target to enhance epithelial wound healingBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2007M Zhao PI3Ks (phosphoinositide-3 kinases) produce PIP3 (phosphatidylinositol(3,4,5)-trisphosphate) which mediates signals for cell survival and proliferation. The tumour suppressor PTEN (phosphatase and tensin homologue) dephosphorylates PIP3 and is a key negative regulator of PI3K signalling. Recent research highlighted important roles for PI3K/PTEN in cell polarization and directional cell migration, pointing to a significant role for PTEN in wound healing where spatially organized tissue growth is essential. Lai et al. (in this issue of British Journal of Pharmacology) have moved a step closer in utilizing PTEN for wound healing through pharmacological inhibition. Two vanadium derivative inhibitors targeting PTEN significantly elevated the level of phosphorylated Akt (protein kinase B) and nearly doubled the wound healing rate in monolayer cultures of lung and airway epithelial cells. Damage to airway and lung epithelia underlies a wide spectrum of significant clinical conditions. With further experiments, this promising approach may find potential clinical use in situations where enhanced wound healing of pulmonary and other epithelia is important. British Journal of Pharmacology (2007) 152, 1141,1144; doi:10.1038/sj.bjp.0707503; published online 8 October 2007 [source] The crucial role of metal ions in neurodegeneration: the basis for a promising therapeutic strategyBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2005Alessandra Gaeta The variety of factors and events involved in neurodegeneration renders the subject a major challenge. Neurodegenerative disorders include a number of different pathological conditions, which share similar critical metabolic processes, such as protein aggregation and oxidative stress, both of which are associated with the involvement of metal ions. In this review, Alzheimer's disease, Parkinson's disease and prion disease are discussed, with the aim of identifying common trends underlying these devastating neurological conditions. Chelation therapy could be a valuable therapeutic approach, since metals are considered to be a pharmacological target for the rationale design of new therapeutic agents directed towards the treatment of neurodegeneration. British Journal of Pharmacology (2005) 146, 1041,1059. doi:10.1038/sj.bjp.0706416 [source] Nuclear magnetic resonance studies of CXC chemokine receptor 4 allosteric peptide agonists in solutionCHEMICAL BIOLOGY & DRUG DESIGN, Issue 2005O.K. Baryshnikova Abstract:, CXC chemokine receptor 4 (CXCR4) is an important pharmacological target due to its involvement in HIV-1 pathogenesis and cancer metastasis. Two recently discovered allosteric agonists that bind and activate CXCR4, the ASLW and RSVM peptides, were analyzed using solution nuclear magnetic resonance spectroscopy. Both peptides assumed an extended backbone conformation with several well-defined local motifs in the regions from residues 5 to 8 and 9 to 12. The local structures in the region of residues 5,8 were different for agonists studied here and natural ligands. The local structure in the region 9,12 was adopted by the entire ensemble of the ASLW peptide structures and by the subset of conformations for the RSVM peptide. The same turn was found in full-length stromal derived factor (SDF)-1 and in the small family of the SDF-1 N-terminal 17-mer. Similar examples in literature suggest the relevance of nascent structures in peptides to their biologically relevant conformations. The significance of found local structures and implications for further drug design are discussed. [source] Addressing Central Nervous System (CNS) Penetration in Drug Discovery: Basics and Implications of the Evolving New ConceptCHEMISTRY & BIODIVERSITY, Issue 11 2009Andreas Reichel Abstract Despite enormous efforts, achieving a safe and efficacious concentration profile in the brain remains one of the big challenges in central nervous system (CNS) drug discovery and development. Although there are multiple reasons, many failures are due to underestimating the complexity of the brain, also in terms of pharmacokinetics (PK). To this day, PK support of CNS drug discovery heavily relies on improving the blood,brain barrier (BBB) permeability in vitro and/or the brain/plasma ratio (Kp) in vivo, even though neither parameter can be reliably linked to pharmacodynamic (PD) and efficacy readouts. While increasing BBB permeability may shorten the onset of drug action, an increase in the total amount in brain may not necessarily increase the relevant drug concentration at the pharmacological target. Since the traditional Kp ratio is based on a crude homogenization of brain tissue, it ignores the compartmentalization of the brain and an increase favors non-specific binding to brain lipids rather than free drug levels. To better link exposure/PK to efficacy/PD and to delineate key parameters, an integrated approach to CNS drug discovery is emerging which distinguishes total from unbound brain concentrations. As the complex nature of the brain requires different compartments to be considered when trying to understand and improve new compounds, several complementary parameters need to be measured in vitro and in vivo, and integrated into a coherent model of brain penetration and distribution. The new paradigm thus concentrates on finding drug candidates with the right balance between free fraction in plasma and brain, and between rate and extent of CNS penetration. Integrating this data into a coherent model of CNS distribution which can be linked to efficacy will allow it to design compounds with an optimal mix in physicochemical, pharmacologic, and pharmacokinetic properties, ultimately mitigating the risk for failures in the clinic. [source] Combining Computational and Biochemical Studies for a Rationale on the Anti-Aromatase Activity of Natural PolyphenolsCHEMMEDCHEM, Issue 12 2007Marco Abstract Aromatase, an enzyme of the cytochrome,P450 family, is a very important pharmacological target, particularly for the treatment of breast cancer. The anti-aromatase activity of a set of natural polyphenolic compounds was evaluated in,vitro. Strong aromatase inhibitors including flavones, flavanones, resveratrol, and oleuropein, with activities comparable to that of the reference anti-aromatase drug aminoglutethimide, were identified. Through the application of molecular modeling techniques based on grid-independent descriptors and molecular interaction fields, the major physicochemical features associated with inhibitory activity were disclosed, and a putative virtual active site of aromatase was proposed. Docking of the inhibitors into a 3D homology model structure of the enzyme defined a common binding mode for the small molecules under investigation. The good correlation between computational and biological results provides the first rationalization of the anti-aromatase activity of polyphenolic compounds. Moreover, the information generated in this approach should be further exploited for the design of new aromatase inhibitors. [source] Targeting leukocyte trafficking to inflamed skin , still an attractive therapeutic approach?EXPERIMENTAL DERMATOLOGY, Issue 1 2007Thomas M. Zollner Abstract:, Research into leukocyte trafficking and its therapeutic exploitation appears to be a multistep process, just like the trafficking cascade itself. The initial euphoria evoked by an early understanding of the trafficking steps was followed by considerable disappointment following the clinical failure of the first selectin antagonist Cylexin (CY-1503), a sialyl LewisX mimetic. The research area recovered and identified additional attractive pharmacological targets such as chemokine receptors and integrins. However, after lack of efficacy in anti-chemokine trials and the fatalities associated with anti VLA-4 therapy (Tysabri), the question arose again whether targeting leukocyte trafficking is really promising or whether such a complex, multistep process with many redundant and/or functionally overlapping molecules is simply too challenging to deal with. In this article, we delineate some pros and cons of this approach followed by a brief update on where we stand in the field and where we might move in the future. [source] Dopaminergic and non-dopaminergic pharmacological hypotheses for gait disorders in Parkinson's diseaseFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2010David Devos Abstract Gait disorders form one component of the axial disorders observed in Parkinson's disease (PD). Indeed, short steps with a forward-leaning stance are diagnostic criteria for PD in the early stages of the condition. Gait disorders also represent a major source of therapeutic failure in the advanced stages of PD (with the appearance of freezing of gait and falls) because they do not respond optimally to the two hand late-stage therapeutics , levodopa and electrical subthalamic nucleus (STN) stimulation. The late onset of doparesistance in these disorders may be linked to propagation of neurodegeneration to structures directly involved in gait control and to non-dopaminergic neurotransmitter systems. The coeruleus locus (a source of noradrenaline) is rapidly and severely affected, leading to a major motor impact. The pedunculopontine nucleus (PPN) and lateral pontine tegmentum (rich in acetylcholine) are both involved in gait. Degenerative damage to the serotoninergic raphe nuclei appears to be less severe, although serotonin-dopamine interactions are numerous and complex. Lastly, dopaminergic depletion leads to glutamatergic hyperactivity of the efferent pathways from the the STN to the PPN. However, the relationships between the various parkinsonian symptoms (and particularly gait disorders) and these pharmacological targets have yet to be fully elucidated. The goal of this review is to develop the various pathophysiological hypotheses published to date, in order to underpin and justify ongoing fundamental research and clinical trials in this disease area. [source] Importance of arterial stiffness as cardiovascular risk factor for future development of new type of drugsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2008Pierre Boutouyrie Abstract Cardiovascular risk prediction relies on classical risk factors such as age, gender, lipids, hypertension, smoking and diabetes. Although the value of such scales of risk is high for populations, its value for individual is reduced and too much influenced by non-modifiable risk factors (age and gender). Biomarkers of risk have been deceiving and genome wide scan approach is too recent. Target organ damage may help in selecting patients at high risk and in determining intervention. Aortic pulse wave velocity, an index of aortic stiffness, has been widely validated as providing additional risk predictions beyond and above classical risk factors, and has now entered into official guidelines. Many interventions (dietary, behaviour, drug treatment) were shown to influence arterial stiffness positively, but little evidence of a direct effect of intervention on arterial stiffness independent of blood pressure is available. New pharmacological targets and new drugs need to be identified. To become a surrogate endpoint for drug development, there is a need to demonstrate that regression arterial stiffness is associated with improved outcome. In parallel to this demonstration, points to be improved are the homogenization and spreading of the technique of measurement, the establishment of a reference value database. [source] Signaling mechanisms in skeletal muscle: Acute responses and chronic adaptations to exerciseIUBMB LIFE, Issue 3 2008Katja S.C. Röckl Abstract Physical activity elicits physiological responses in skeletal muscle that result in a number of health benefits, in particular in disease states, such as type 2 diabetes. An acute bout of exercise/muscle contraction improves glucose homeostasis by increasing skeletal muscle glucose uptake, while chronic exercise training induces alterations in the expression of metabolic genes, such as those involved in muscle fiber type, mitochondrial biogenesis, or glucose transporter 4 (GLUT4) protein levels. A primary goal of exercise research is to elucidate the mechanisms that regulate these important metabolic and transcriptional events in skeletal muscle. In this review, we briefly summarize the current literature describing the molecular signals underlying skeletal muscle responses to acute and chronic exercise. The search for possible exercise/contraction-stimulated signaling proteins involved in glucose transport, muscle fiber type, and mitochondrial biogenesis is ongoing. Further research is needed because full elucidation of exercise-mediated signaling pathways would represent a significant step toward the development of new pharmacological targets for the treatment of metabolic diseases such as type 2 diabetes. © 2008 IUBMB IUBMB Life, 60(3): 145,153, 2008 [source] Putative role of proteolysis and in,ammatory response in the toxicity of nerve and blister chemical warfare agents: implications for multi-threat medical countermeasures,JOURNAL OF APPLIED TOXICOLOGY, Issue 3 2003F. M. Cowan Abstract Despite the contrasts in chemistry and toxicity, for blister and nerve chemical warfare agents there may be some analogous proteolytic and in,ammatory mediators and pathological pathways that can be pharmacological targets for a single-drug multi-threat medical countermeasure. The dermal,epidermal separation caused by proteases and bullous diseases compared with that observed following exposure to the blister agent sulfur mustard (2,2,-dichlorodiethyl sul,de) has fostered the hypothesis that sulfur mustard vesication involves proteolysis and in,ammation. In conjunction with the paramount toxicological event of cholinergic crisis that causes acute toxicity and precipitates neuronal degeneration, both anaphylactoid reactions and pathological proteolytic activity have been reported in nerve-agent-intoxicated animals. Two classes of drugs already have demonstrated multi-threat activity for both nerve and blister agents. Serine protease inhibitors can prolong the survival of animals intoxicated with the nerve agent soman and can also protect against vesication caused by the blister agent sulfur mustard. Poly (ADP-ribose) polymerase (PARP) inhibitors can reduce both soman-induced neuronal degeneration and sulfur-mustard-induced epidermal necrosis. Protease and PARP inhibitors, like many of the other countermeasures for blister and nerve agents, have potent primary or secondary anti-in,ammatory pharmacology. Accordingly, we hypothesize that drugs with anti-in,ammatory actions against either nerve or blister agent might also display multi-threat ef,cacy for the in,ammatory pathogenesis of both classes of chemical warfare agent. Published in 2003 by John Wiley & Sons, Ltd. [source] Recent cancer drug development with xanthone structuresJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2009Younghwa Na Abstract Objectives Xanthones are simple three-membered ring compounds that are mainly found as secondary metabolites in higher plants and microorganisms. Xanthones have very diverse biological profiles, including antihypertensive, antioxidative, antithrombotic and anticancer activity, depending on their diverse structures, which are modified by substituents on the ring system. Although several reviews have already been published on xanthone compounds, few of them have focused on the anticancer activity of xanthone derivatives. In this review we briefly summarize natural and synthetic xanthone compounds which have potential as anticancer drugs. Key findings The interesting structural scaffold and pharmacological importance of xanthone derivatives have led many scientists to isolate or synthesize these compounds as novel drug candidates. In the past, extensive research has been conducted to obtain xanthone derivatives from natural resources as well as through synthetic chemistry. Xanthones interact with various pharmacological targets based on the different substituents on the core ring. The anticancer activities of xanthones are also dramatically altered by the ring substituents and their positions. Summary The biological activities of synthetic xanthone derivatives depend on the various substituents and their position. Study of the biological mechanism of action of xanthone analogues, however, has not been conducted extensively compared to the diversity of xanthone compounds. Elucidation of the exact biological target of xanthone compounds will provide better opportunities for these compounds to be developed as potent anticancer drugs. At the same time, modification of natural xanthone derivatives aimed at specific targets is capable of expanding the biological spectrum of xanthone compounds. [source] The relationship between the electrospray ionization behaviour and biological activity of some phosphino Cu(I) complexesRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 11 2010Francesco Tisato Electrospray ionization mass spectrometry was usefully employed for the characterization of three phosphino copper(I) complexes of medicinal interest. This technique revealed that the original [CuL4]+ pro-drugs (L,=,hydrophilic tertiary phosphine) underwent dissociation with production of coordinative unsaturated [CuL3]+ and [CuL2]+ species, which represented key intermediates for the activation of potential biological properties. The more favoured was the displacement of the ligands from the [CuL4]+ parent complex, the more favoured was in turn the possibility for the metal ion to directly interact with biological substrates, including pharmacological targets related to cancer proliferation. An inverse correlation between the stability and the cytotoxic activity of the three copper(I) complexes investigated has been clearly established. Copyright © 2010 John Wiley & Sons, Ltd. [source] N -Acyl amino acids and N -acyl neurotransmitter conjugates: neuromodulators and probes for new drug targetsBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2010Mark Connor The myriad functions of lipids as signalling molecules is one of the most interesting fields in contemporary pharmacology, with a host of compounds recognized as mediators of communication within and between cells. The N -acyl conjugates of amino acids and neurotransmitters (NAANs) have recently come to prominence because of their potential roles in the nervous system, vasculature and the immune system. NAAN are compounds such as glycine, GABA or dopamine conjugated with long chain fatty acids. More than 70 endogenous NAAN have been reported although their physiological role remains uncertain, with various NAAN interacting with a low affinity at G protein coupled receptors (GPCR) and ion channels. Regardless of their potential physiological function, NAAN are of great interest to pharmacologists because of their potential as flexible tools to probe new sites on GPCRs, transporters and ion channels. NAANs are amphipathic molecules, with a wide variety of potential fatty acid and headgroup moieties, a combination which provides a rich source of potential ligands engaging novel binding sites and mechanisms for modulation of membrane proteins such as GPCRs, ion channels and transporters. The unique actions of subsets of NAAN on voltage-gated calcium channels and glycine transporters indicate that the wide variety of NAAN may provide a readily exploitable resource for defining new pharmacological targets. Investigation of the physiological roles and pharmacological potential of these simple lipid conjugates is in its infancy, and we believe that there is much to be learnt from their careful study. [source] Guide to Receptors and Channels (GRAC)BRITISH JOURNAL OF PHARMACOLOGY, Issue 2009British Journal of Clinical Pharmacology The fourth edition of the Guide to Receptors and Channels is a compilation of the major pharmacological targets divided into seven sections: 7-transmembrane receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside suggestions for further reading. [source] Do studies in caveolin-knockouts teach us about physiology and pharmacology or instead, the ways mice compensate for ,lost proteins'?BRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2007P A Insel A wide array of phenotypic changes have been reported in mice with knockout of expression of caveolin-1. Neidhold et al. (2007) describe results in this issue that continue this trend by showing that saphenous arteries from adult caveolin-1 knockout mice lack caveolae, lose ,1 -adrenoceptor-promoted relaxation, gain ,3 -adrenoceptor-promoted relaxation but show no change in vasomotor response to ,2 -adrenoceptor activation. Neither the physiological importance for wild-type animals nor the mechanistic basis for these changes is clear. Although the caveolin-1 knockout and wild-type mice express similar levels of the receptor mRNAs, the protein expression of the receptors is not specified and represents, in our view, an important limitation of the study. We also question the physiological relevance of the findings and ask: Do studies in total body/lifespan caveolin-knockout mice further understanding of physiology and pharmacology or do they primarily characterize secondary consequences? We propose that alternative approaches that decrease caveolin expression in a temporally and spatially discrete manner are more likely to facilitate definitive conclusions regarding caveolin-1 and its role in regulation of , -adrenoceptors and other pharmacological targets. British Journal of Pharmacology (2007) 150, 251,254. doi:10.1038/sj.bjp.0706981 [source] ILLUMINATING THE STRUCTURE AND FUNCTION OF CYS-LOOP RECEPTORSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 10 2008Stephan A Pless SUMMARY 1Cys-loop receptors are an important class of ligand-gated ion channels. They mediate fast synaptic neurotransmission, are implicated in various ,channelopathies' and are important pharmacological targets. Recent progress in X-ray crystallography and electron microscopy has provided a considerable insight into the structure of Cys-loop receptors. However, data from these experiments only provide ,snapshots' of the proteins under investigation. They cannot provide information about the various conformations the protein adopts during transition from the closed to the open and desensitized states. 2Voltage-clamp fluorometry helps overcome this problem by simultaneously monitoring movements at the channel gate (through changes in current) and conformational rearrangements in a domain of interest (through changes in fluorescence) in real time. Thus, the technique can provide information on both transitional and steady state conformations and serves as a real time correlate of the channel structure and its function. 3Voltage-clamp fluorometry experiments on Cys-loop receptors have yielded a large body of data concerning the mechanisms by which agonists, antagonists and modulators act on these receptors. They have shed new light on the conformational mobility of both the ligand-binding and the transmembrane domain of Cys-loop receptors. [source] | ||||||||||||||||