Pharmaceutica acta Helvetiae最新文献

{"title":"Kappa opioid agonists as targets for pharmacotherapies in cocaine abuse","authors":"John L. Neumeyer ,&nbsp;Nancy K. Mello ,&nbsp;S. Stevens Negus ,&nbsp;Jean M. Bidlack","doi":"10.1016/S0031-6865(99)00044-8","DOIUrl":"10.1016/S0031-6865(99)00044-8","url":null,"abstract":"<div><p><span><span><span>Kappa opioid receptors derive their name from the prototype </span>benzomorphan, </span>ketocyclazocine (</span><strong>1a</strong><span>) which was found to produce behavioral effects that were distinct from the behavioral effects of morphine but that were antagonized by the opioid antagonist<span><span>, naltrexone. Recent evidence suggests that agonists and antagonists at kappa opioid receptors may modulate the activity of </span>dopaminergic<span> neurons and alter the neurochemical and behavioral effects of cocaine. Kappa agonists<span><span> blocked the effects of cocaine in squirrel monkeys in studies of cocaine discrimination and scheduled-controlled responding. Studies in rhesus monkeys suggested that kappa opioids may antagonize the reinforcing effects of cocaine. These studies prompted the synthesis and evaluation of a series of kappa agonists related to the </span>morphinan, </span></span></span></span><span>l</span>-cyclorphan (<strong>3a</strong>) and the benzomorphan, <span>l</span>-cyclazocine (<strong>2</strong>). We describe the synthesis and preliminary evaluation of a series of morphinans, structural analogs of cyclorphan <strong>3a–c</strong>, the 10-keto morphinans <strong>4a</strong> and <strong>b</strong>, and the 8-keto benzomorphan <strong>1b</strong>, structurally related to ketocyclazocine (<strong>1a</strong>). In binding experiments <span>l</span>-cyclorphan (<strong>3a</strong>), the cyclobutyl (<strong>3b</strong>), the tetrahydrofurfuryl <strong>3c</strong> and the 10-keto <strong>4b</strong> analogs had high affinity for <em>mu</em> (μ), <em>delta</em> (δ) and <em>kappa</em> (κ) opioid receptors. Both <strong>3a</strong> and <strong>3b</strong><span> were more selective for the κ receptor than the μ receptor. However, </span><strong>3b</strong><span> was 18-fold more selective for the κ receptor in comparison to the δ receptor, while cyclorphan (</span><strong>3a</strong>) had only a 4-fold greater affinity for the κ receptor in comparison to the δ receptor. The cyclobutyl compound <strong>3b</strong><span> was found to have significant μ agonist properties, while </span><strong>3a</strong><span> was a μ antagonist. All compounds were also examined in the mouse tail flick and writhing assay. Compounds </span><strong>3a</strong> and <strong>3b</strong> were κ agonists. Correlating with the binding results, compound <strong>3a</strong><span> had some δ agonist properties, while </span><strong>3b</strong> was devoid of any activity at the δ receptor. In addition, compounds <strong>3a</strong> and <strong>3b</strong> had opposing properties at the μ opioid receptor. The cyclobutyl compound <strong>3b</strong> was found to have significant μ agonist properties, while <strong>3a</strong> was a μ antagonist.</p></div>","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 337-344"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00044-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21660311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Central nicotinic receptor ligands and pharmacophores","authors":"Richard A Glennon,&nbsp;Małgorzata Dukat","doi":"10.1016/S0031-6865(99)00022-9","DOIUrl":"10.1016/S0031-6865(99)00022-9","url":null,"abstract":"<div><p>Multiple populations of pentameric nicotinic acetylcholinergic (nACh) receptors exist and several may be classified as central or neuronal. Neuronal nACh receptors, however, are primarily of the α₄β₂ and α₇ types, and these have been the focus of most recent investigations aimed at the development of novel agents and identification of pharmacophores. Selectivity data are limited. Furthermore, because several populations of nACh receptors might indirectly influence a given functional effect, it is difficult to discuss structure–activity relationships (SAR) in terms of differential SAR, or to formulate SAR on the basis of functional studies. For the most part, studies are limited to the formulation of structure–affinity relationships (SAFIR) for the binding of agents at nACh receptors, and for these the α₄β₂ population has been the most extensively investigated. SAFIR and newer agents are reviewed here with reference to earlier studies. Novel agents now have been identified that bind with up to 30 times higher affinity than nicotine and these are providing new insight into the understanding of nACh receptors.</p></div>","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 103-114"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00022-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21659451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and development of selective muscarinic agonists for the treatment of Alzheimer's disease: characterization of tetrahydropyrimidine derivatives and development of new approaches for improved affinity and selectivity for M1 receptors","authors":"William S. Messer Jr.,&nbsp;W.G. Rajeswaran,&nbsp;Yang Cao,&nbsp;Hai-Jun Zhang,&nbsp;Afif A. El-Assadi,&nbsp;Colleen Dockery,&nbsp;Jill Liske,&nbsp;John O'Brien,&nbsp;Frederick E. Williams,&nbsp;Xi-Ping Huang,&nbsp;Mary E. Wroblewski,&nbsp;Peter I. Nagy,&nbsp;Steven M. Peseckis","doi":"10.1016/S0031-6865(99)00026-6","DOIUrl":"10.1016/S0031-6865(99)00026-6","url":null,"abstract":"<div><p><span><span>Cholinergic neurons degenerate in </span>Alzheimer's disease<span>, resulting in cognitive impairments and memory deficits, and drug development efforts have focused on selective M</span></span>₁<span><span> muscarinic agonists. 5-(3-Ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine </span>trifluoroacetic acid (CDD-0102) stimulates M</span>₁<span> muscarinic receptors in rat brain [Messer, W.S., Jr., Abuh, Y.F., Liu, Y., Periyasamy, S., Ngur, D.O., Edgar, M.A., El-Assadi, A.A., Sbeih, S., Dunbar, P.G., Roknich, S., Rho, T., Fang, Z., Ojo, B., Zhang, H., Huzl, J.J., III, Nagy, P.I., 1997a. J. Med. Chem. 40, 1230–1246.] and improves memory function in rats with lesions of the basal forebrain cholinergic system. Moreover, CDD-0102 exhibits oral bioavailability, few side effects and low toxicity, and thus represents a viable candidate for clinical studies. Despite the development of functionally selective agonists such as xanomeline and CDD-0102, there is room for improvements in ligand affinity and selectivity. The high degree of amino acid homology within transmembrane domains has hindered the development of truly selective agonists. Site-directed mutagenesis, biochemical and molecular modeling studies have identified key amino acid residues such as Thr192 and Asn382 in the binding of agonists to M</span>₁ receptors [Huang, X.P., Nagy, P.I., Williams, F.E., Peseckis, S.M., Messer, W.S., Jr., 1999. Br. J. Pharmacol. 126, 735–745.]. Recent work has implicated residues at the top of transmembrane domain VI in the binding of muscarinic agonists and activation of M₁ receptors [Huang, X.P., Williams, F.E., Peseckis, S.M., Messer, W.S., Jr., 1998. J. Pharmacol. Exp. Ther. 286, 1129–1139.]. Thus, residues such as Ser388 represent molecular targets for the further development of agonists with improved M₁ receptor affinity, selectivity and activity.</p></div>","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 135-140"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00026-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21659455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"α1-Adrenoreceptor antagonists bearing a quinazoline or a benzodioxane moiety","authors":"C Melchiorre ,&nbsp;P Angeli ,&nbsp;M.L Bolognesi ,&nbsp;A Chiarini ,&nbsp;D Giardinà ,&nbsp;U Gulini ,&nbsp;A Leonardi ,&nbsp;G Marucci ,&nbsp;A Minarini ,&nbsp;M Pigini ,&nbsp;W Quaglia ,&nbsp;M Rosini ,&nbsp;V Tumiatti","doi":"10.1016/S0031-6865(99)00049-7","DOIUrl":"10.1016/S0031-6865(99)00049-7","url":null,"abstract":"","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 181-190"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00049-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21659332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sigma receptors: recent advances and new clinical potentials","authors":"Wayne D Bowen","doi":"10.1016/S0031-6865(99)00034-5","DOIUrl":"10.1016/S0031-6865(99)00034-5","url":null,"abstract":"<div><p><span>Several recent advances are leading to a better understanding of sigma receptors. Here we focus on our recent findings regarding cellular functions of sigma-2 receptors and discuss their possible clinical implications. Agonists at sigma-2 receptors induced changes in cell morphology and apoptosis in various cell types. Sigma-2 receptor activation produced both transient and sustained increases in [Ca</span>⁺⁺]i, derived from different intracellular stores. These changes in [Ca⁺⁺<span>]i and cytotoxic effects are mediated by intracellular sigma-2 receptors. Sigma-2 agonists induced apoptosis in drug-resistant cancer cells, enhanced the potency of DNA damaging agents, and down-regulated expression of p-glycoprotein mRNA. Thus, sigma-2 receptor agonists may be useful in treatment of drug-resistant cancers. Sigma radioligands have been used in tumor imaging. We also discuss how sigma-2 antagonists might prevent the irreversible motor side effects of typical neuroleptics. Sigma-2 receptors may subserve a novel signalling pathway to apoptosis, involved in regulation of cell proliferation and/or viability.</span></p></div>","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 211-218"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00034-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21659336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nicotinic systems in central nervous systems disease: degenerative disorders and beyond","authors":"Paul A Newhouse,&nbsp;Megan Kelton","doi":"10.1016/S0031-6865(99)00047-3","DOIUrl":"10.1016/S0031-6865(99)00047-3","url":null,"abstract":"<div><p><span><span><span>Advances in the understanding of the structure, function, and distribution of central nervous system (CNS) nicotinic receptors has provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realization that such receptors are changed in degenerative </span>neurologic diseases such as </span>Alzheimer's disease<span> (AD) and Parkinson's disease<span> (PD). Ongoing investigations of the molecular substructure of CNS nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioral, motor, and sensory functioning. Clues from careful studies of human cognition and behavior are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents. Modulation of these receptors with the ultimate goal of producing therapeutic benefits is the goal of these investigations and drug development. This paper will review studies from our laboratory and others that point to the importance of CNS nicotinic mechanisms in normal human cognitive and behavioral functioning as well as their role in disease states. In addition, this paper will examine potential clinical applications of nicotine and/or nicotinic agonists in a variety of </span></span></span>CNS disorders<span><span> with particular emphasis on structural brain disease including: movement disorders such as Parkinson's disease and </span>Tourette's syndrome<span>, cognitive/behavioral disorders such as Alzheimer's disease, attention deficit/hyperactivity disorder, and schizophrenia, and other more speculative applications. Important results from early therapeutic studies of nicotine and/or nicotinic agonists in these disease states are presented. For example, recent studies with nicotine and novel nicotinic agonists such as ABT-418 by our group in AD patients suggest that nicotinic stimulation can improve the acquisition and retention of verbal information and decrease errors. Preliminary results from a series of studies examining the acute and subchronic quantitative effects of nicotine on cognitive and motor functioning in Parkinson's disease suggest that acute nicotine administration and stimulation improves some aspects of cognitive and motor performance and may improve the processing speed of more complex tasks. The most likely near-term applications of novel nicotinic agonists in CNS disorders are likely to be in those disorders that are degenerative in nature, e.g. Parkinson's disease and Alzheimer's disease, or other movement disorders such as Tourette's syndrome. The most likely direct therapeutic role for nicotinic agonists is as augmentation therapy in combination with other agents rather than as monotherapy, except earl","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 91-101"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00047-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21659450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CI-1017, a functionally M1-selective muscarinic agonist: design, synthesis, and preclinical pharmacology","authors":"H Tecle,&nbsp;R.D Schwarz,&nbsp;S.D Barrett,&nbsp;M.J Callahan,&nbsp;B.W Caprathe,&nbsp;R.E Davis,&nbsp;P Doyle,&nbsp;M Emmerling,&nbsp;D.J Lauffer,&nbsp;T Mirzadegan,&nbsp;D.W Moreland,&nbsp;W Lipiniski,&nbsp;C Nelson,&nbsp;C Raby,&nbsp;C Spencer,&nbsp;K Spiegel,&nbsp;A.J Thomas,&nbsp;J.C Jaen","doi":"10.1016/S0031-6865(99)00027-8","DOIUrl":"10.1016/S0031-6865(99)00027-8","url":null,"abstract":"<div><p><span>The five muscarinic receptor subtypes (M</span>₁–M₅<span>) are characterized by seven helices that define a transmembrane cavity which serves as the binding pocket for agonists and antagonists. The five cavities appear to be topographically different enough to permit subtype selectivity among antagonists but not among classical agonists which tend to be smaller in size than antagonists. It was reasoned that synthesis of muscarinic agonists longer/larger than their classical counterparts might result in subtype selectivity. M</span>₁ subtype selectivity was found in a class of 1-azabicyclo[2.2.1]heptan-3-one, <em>O</em><span><span>-(3-aryl-2-propynyl) oximes<span>. One of these, CI-1017, improved spatial memory of hippocampally deficient mice and nbM-lesioned rats at doses of 1.0–3.2 and 0.1–0.3 mg/kg, respectively, while producing parasympathetic side effects only at very high doses (100–178 mg/kg). Additionally, CI-1017 inhibited production of amyloidogenic Aβ and increased secretion of soluble APP. Thus, CI-1017, besides treating </span></span>AD symptomatically, may also retard its progression. CI-1017 has recently completed phase I clinical trials.</span></p></div>","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 141-148"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00027-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21659456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The RET receptor tyrosine kinase: activation, signalling and significance in neural development and disease","authors":"Ivor Mason","doi":"10.1016/S0031-6865(99)00048-5","DOIUrl":"10.1016/S0031-6865(99)00048-5","url":null,"abstract":"<div><p><span>The RET receptor tyrosine kinase<span><span> was first identified in a screen for human oncogenes and has subsequently been linked to several human syndromes: Hirschprung's disease, multiple endocrine neoplasia types 2A and 2B and familial </span>thyroid carcinoma. Interestingly, all of the tissues affected by mutations in </span></span><em>RET</em><span><span><span><span><span><span> are derived from the neural crest during development. RET transduces a signal following activation by ligands of the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophins which currently comprises GDNF, neuturin (NTN), </span>artemin (ART) and </span>persephin (PSP). To activate RET they form a tripartite complex with RET and a member of a family of four extracellular, GPI-linked </span>alpha receptors (GFRα1–4). Specificity is achieved by each GFRα binding only one member of the GDNF family with high affinity. Current evidence indicates that signal transduction by RET activates several second messenger systems including the PLCγ, Ras, JNK and </span>inositol phosphate<span> pathways. Targeted mutagenesis in </span></span>transgenic mice<span> has shown that Ret, GFRα1 and GDNF are required for multiple developmental events including development of the enteric nervous system (ENS) affected in Hirschsprung's disease. We describe experiments in chick neural crest cells which provide evidence for the normal function of RET and the basis of the defect in Hirschsprung's disease.</span></span></p></div>","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 261-264"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00048-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21659956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ICAM-1 receptors and cold viruses","authors":"Jordi Bella ,&nbsp;Michael G Rossmann","doi":"10.1016/S0031-6865(99)00056-4","DOIUrl":"10.1016/S0031-6865(99)00056-4","url":null,"abstract":"<div><p>Human rhinoviruses (HRVs), the single most important etiologic agent of common colds, are small viruses composed of an icosahedral protein shell that encapsidates a single, positive RNA strand. Multiplication of HRVs occurs in the cytoplasm of the host cell. To produce infection, HRVs must first attach to specific cellular receptors embedded in the plasma membrane. Ninety percent of HRVs immunogenic variants use as receptor intercellular adhesion molecule-1 (ICAM-1), a cell surface glycoprotein that promotes intercellular signaling in processes derived from inflammation response. As HRV receptor, ICAM-1 positions the virus to within striking distance of the membrane, and then triggers a conformational change in the virus that ultimately results in delivery of the viral RNA genome into the cytoplasm, across a lipid bilayer. The interaction between ICAM-1 and HRVs has been analyzed by the combination of crystal structures of HRVs and ICAM-1 fragments with electron microscopy reconstructions of the complexes. The resulting molecular models are useful to address questions about receptor recognition, binding specificity, and mechanisms by which ICAM-1 induces virus uncoating.</p></div>","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 291-297"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00056-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21660304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"General topics and perspectives","authors":"H Timmerman","doi":"10.1016/S0031-6865(99)00057-6","DOIUrl":"10.1016/S0031-6865(99)00057-6","url":null,"abstract":"","PeriodicalId":19830,"journal":{"name":"Pharmaceutica acta Helvetiae","volume":"74 2","pages":"Pages 313-314"},"PeriodicalIF":0.0,"publicationDate":"2000-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0031-6865(99)00057-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21660306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}