bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacogenomics and animal models of schizophrenia
Authors: Klink Ruby , Boksa Patricia , Joober Ridha
Published: September 2003

Schizophrenia is a syndromal brain disease of largely unknown pathophysiology and most likely heterogeneous etiology in which genetic predisposition constitutes the major risk factor. In recent years, a shift from a monolithic view of the disorder is leading to its dissection into component phenotypic modules or endophenotypes that may differ in pathophysiology, underlying genetic diathesis, or treatment response. Reducing phenotypic heterogeneity by focusing on endophenotypes will facilitate the production of valid animal models to be used in experimental approaches, improve our chances of uncovering genes predisposing to the disease in linkage or association approaches, and simplify generation of novel molecular targets for the drug discovery process. We hereby review some recently generated mouse models that replicate specific endophenotypes observed in schizophrenia and that implicate putative contributing genes that may be exploited to explore novel drug targets. These are derived from opposing but complementary perspectives. One approach developed in our work begins with mouse models of schizophrenia traits to uncover candidate schizophrenia genes. Another approach followed by several other groups begins with putative schizophrenia vulnerability genes to investigate the corresponding endophenotype in mouse models. Combined with global analysis of gene expression, these mouse models offer the hope that the disease‐causing and treatment pathways implicated in schizophrenia will finally be unraveled. Drug Dev. Res. 60:95–103, 2003. © 2003 Wiley‐Liss, Inc.
Pharmacogenetic and pharmacogenomic research for the prediction of response to antipsychotics in schizophrenia
Authors: Arranz M.J. , Kerwin R.W.
Published: September 2003

Treatment of schizophrenia sufferers requires the use of antipsychotic drugs. First developed in the 1950s, two major types of antipsychotics are currently available: classical or conventional antipsychotics and atypical antipsychotics. Selection of treatment is based on trial and error strategies with a detrimental effect on patients' prognosis and chances of recovery. Clinical and genetic indicators have been investigated as predictors of response to antipsychotic treatment. Several studies have reported association between clinical observations and treatment outcome. However, clinical indicators require post‐treatment information that may delay selection of a beneficial drug. Alternatively, genetic polymorphisms have been suggested as useful pre‐treatment predictors. In the last decade, pharmacogenetic researchers have reported numerous associations between antipsychotic response and polymorphisms in genes coding for drug‐targeted receptors and metabolic enzymes. This research has provided information that can be used for the individual prediction of response to specific antipsychotics. Much more is expected from the surge of pharmacogenomic research in pharmaceutical companies. Novel targets for antipsychotic treatment, improved and safer drugs, and individualised treatment are some of the goals expected to achieve in the near future. Drug Dev. Res. 60:104–110, 2003. © 2003 Wiley‐Liss, Inc.
Toward schizophrenia genes: Genetics and transcriptome
Authors: Ito Chihiro , Ouchi Yuta
Published: September 2003

Schizophrenia is highly heritable, and the identification of its genetic factors is receiving great attention. In this review, we digested current genetic findings about schizophrenia. At first, DISC‐1 and ‐2 derived from a large Scottish family, and velo‐cardio‐facial syndrome caused by microdeletion of 22q11, are hot topics in cytogenic studies. Secondly, selections and classifications of samples become the biggest problems in linkage studies, because many following studies failed to confirm replicated linkages. Thirdly, a lot of functional and/or positional candidate genes are analyzed. Some genes, including NRG1, DTNBP1, G72, DAAO, RGS4, and PRODH2, are recently identified in association studies. In the last method, the novel way to select functional candidate genes with a transcriptome analysis is getting presented. The transcriptome analysis makes it possible to identify up‐ and down‐regulated genes from overall transcriptions (mRNAs). We also have an ongoing case‐control study about schizophrenia, following serial analysis of gene expression (SAGE), one of the transcriptome analyses. We analyzed changes of gene expressions in methamphetamine‐ and phencyclidine‐treated rodent cerebral cortexes, two well‐known animal models of schizophrenia. We identified their homologous 209 human genes as candidates. These findings will bring us new understanding of pathophysiologic aspects and further drug targets toward schizophrenia. Drug Dev. Res. 60:111–118, 2003. © 2003 Wiley‐Liss, Inc.
Genetic perspectives of histamine and muscarinic receptors in schizophrenia and clozapine response
Authors: Mancama Dalu , Arranz Maria J. , Kerwin Robert W.
Published: September 2003

The mechanisms that underlie schizophrenia and influence outcome to antipsychotic treatment are unclear, and remain the focus of intense investigation. Genetic studies have been at the forefront of work to delineate the disorders aetiology and have led to the identification of gene variants, predominantly throughout neurotransmitter pathways, that may be important. Prevailing evidence, however, suggests that those variants so far identified confer a relatively limited influence, and in the search to identify the further participants growing evidence has emerged implicating the involvement of histamine and muscarinic receptor pathways. Studies investigating the genetic contribution of these systems in the disorder are relatively nascent, and consequently the extent to which each may be involved is presently unclear. Further work is, therefore, warranted to determine this role, since these pathways potentially offer an unprecedented insight into the disorders aetiology. It is envisaged this knowledge may also contribute to clarifying the mechanisms that moderate antipsychotic efficacy, and could accelerate ongoing efforts to develop new therapies and predictive pharmacogenetic approaches associated with this area of drug treatment. Drug Dev. Res. 60:119–126, 2003. © 2003 Wiley‐Liss, Inc.
Consequences of low levels of nicotinic acetylcholine receptors in schizophrenia for drug development
Authors: Leonard Sherry
Published: September 2003

The incidence of smoking in the mentally ill is much higher than in the general population and is inordinately high in schizophrenia. It has been suggested that this might be an attempt to self‐medicate an underlying biological deficit. The receptors that mediate nicotinic responses are decreased in many regions of postmortem brain in schizophrenic smokers, compared to control smokers. Patients exhibit differential responses to nicotine in a number of behavioral, cognitive, and metabolic measures. As nicotine regulates the release of a large number of neurotransmitters, it is likely that differences in down‐stream neuroadaptation of other transmitter/receptor systems would result from the reduced level of nicotinic receptors in these patients. The disparate responses to nicotine have consequences for the development of cholinergic drug therapies in schizophrenia. Drug Dev. Res. 60:127–136, 2003. © 2003 Wiley‐Liss, Inc.
Glutamate receptor genes as candidates for schizophrenia susceptibility
Authors: Fukumaki Yasuyuki , Shibata Hiroki
Published: September 2003

The glutamatergic dysfunction hypothesis suggests that genes involved in the glutamate neurotransmitter system are candidates for schizophrenia‐susceptibility genes. We have been doing systematic studies of the association of schizophrenia with each member of the glutamate receptor gene family. In this review, we summarize our results of association studies of five glutamate receptor genes, two of which are metabotropic, GRM2 and GRM3, whereas the other four are ionotropic, GRIA4, GRIK1, GRIK2 and GRIN1. Haplotype analyses using combinations of SNPs evenly distributed across the relevant genes showed significant associations of GRM3 and GRIA4 with schizophrenia. We discuss the possible involvement of glutamate receptor genes in the pathogenesis of schizophrenia, on the basis of association as well as linkage and postmortem studies previously reported. Replication of positive associations using different populations and the family‐based study are necessary to confirm the results. Generation of gene‐manipulated mice to represent endophenotypes of schizophrenia would be an alternative way to verify susceptibility genes. Some members of the glutamate receptor family may be promising targets for schizophrenia drugs. Drug Dev. Res. 60:137–151, 2003. © 2003 Wiley‐Liss, Inc.
Pharmacogenetics and association studies in schizophrenia
Authors: Ntzani Evangelia E. , Ioannidis John P. A.
Published: September 2003

We present an overview of the contribution of genetic association studies on understanding schizophrenia pharmacogenomics. Using a MEDLINE search (March 2003), we identified 96 reports on genetic associations of diverse polymorphisms with response to therapy or adverse events from antipsychotics. Most studies have targeted polymorphisms in the cytochrome p450 metabolizing gene system, the dopamine receptor genes, and the serotonin receptors and serotonin transporter genes, but an increasing number of new gene targets is added continuously. We could identify more than 2 published reports only for 16 pharmacogenetic associations, and only 10 of them have had more than 3 published reports. Most of these studies have had small sample size and none recruited >1,000 patients with schizophrenia. Sample size exceeded 600 patients in 3 reports by the same team and no significant association has been found in these reports for 9 distinct polymorphisms of the DRD2 gene, two polymorphisms of the serotonin transporter gene, or the 48‐bp VNTR polymorphism of the DRD4 gene. Meta‐analyses of the 102‐T/C and the His452Tyr polymorphisms of the HTR2A gene and of the Ser9Gly polymorphism of the DRD3 gene suggest a significant association with therapeutic response that is, nevertheless, no longer formally statistically significant when the first, hypothesis‐generating study is excluded. Genetic association studies are a valuable tool in schizophrenia pharmacogenetic research. However, large, carefully conducted studies with appropriately defined analysis and outcomes and full reporting, as well as validation of associations across several studies, are essential for creating a rational knowledge base in this field. Drug Dev. Res. 60:152–163, 2003. © 2003 Wiley‐Liss, Inc.
Refining pharmacogenetic research in schizophrenia: Control for patient‐related variables
Authors: Lane Hsien‐Yuan , Chang Yue‐Cune , Huang Chieh‐Liang , Chang Wen‐Ho
Published: September 2003

There is strong evidence to suggest that genetic variation plays an important role in inter‐individual differences in medication response and toxicity. Most of the previous pharmacogenetic studies, however, cannot be reconfirmed. Of note, drug efficacy or side effects depend not only on genetic factors but also on nongenetic factors, such as illness duration, past treatment history, and drug dosage or blood concentration. However, most pharmacogeneticists did not consider or control the possible impact of the nongenetic factors. Schizophrenia is a severe neuropsychiatric disorder with a polygenic mode of inheritance that is also governed by nongenetic factors. Schizophrenia's symptoms are principally subdivided into two subtypes, positive and negative. The positive symptoms include delusions and hallucinations; the negative symptoms, blunted affect and social withdrawal. Atypical antipsychotics are usually superior in the treatment of negative symptoms than typical agents. Although atypical agents are becoming the mainstay for schizophrenia treatment, what makes an antipsychotic “atypical” remains unclear. One of our recent studies have simultaneously evaluated the effects of genetic and nongenetic determinants on the efficacy of risperidone (a widely used atypical antipsychotic agent). We found that 5‐HT2A receptor 102‐T/C polymorphism could predict clinical response (mainly for negative symptoms rather than positive symptoms) in schizophrenia. Among nongenetic factors, fewer previous hospitalizations and higher risperidone dosage also predicted better treatment response after control for the 102‐T/C polymorphism and other confounders. It is hoped that this novel study model could revolutionize future research in pharmacogenetics or other fields of genetics. Drug Dev. Res. 60:164–171, 2003. © 2003 Wiley‐Liss, Inc.
Chemistry of Sulfonate‐ and Sulfonamide‐Stabilized Carbanions − The CSIC Reactions
Authors: Postel Denis , Van Nhien Albert Nguyen , Marco José L.
Published: September 2003

In this account we review the varied, but extensively documented reactions affording acyclic alkanesulfonates, alkanesulfonamides, and heterocyclic ring systems (sultones, 1,2‐oxathiole S,S‐dioxides, sultams, and 2,3‐dihydroisothiazole S,S‐dioxides) from conveniently functionalized alkanesulfonates or alkanesulfonamides, by a general procedure that we have named and classified as CSIC reactions both as intermolecular [Carbanion‐mediated Sulfonate (or Sulfonamide) Intermolecular Coupling] and as intramolecular [Carbanion‐mediated Sulfonate (or Sulfonamide) Intramolecular Cyclization] variants of the conversion. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Conception, Characterization and Correlation of New Marine Odorants
Authors: Kraft Philip , Eichenberger Walter
Published: September 2003

Via a synthetic sequence consisting of PPA‐mediated Friedel−Crafts acylation of veratrol (8), Clemmensen reduction, demethylation with TMSI, Williamson ether synthesis employing 3‐chloro‐2‐(chloromethyl)prop‐1‐ene and in‐situ ruthenium tetroxide oxidation, numerous substituted benzo[b][1,4]dioxepinones 15−27 and 2,3‐dihydro‐1H‐5,9‐dioxacyclohepta[f]indenones 7, 13 and 14 were prepared to study their odor−structure correlation. In the course of these studies, we discovered the extremely powerful new marine odorant 7‐(3′‐methylbutyl)benzo[b][1,4]dioxepin‐3‐one (16). On the basis of the measured odor threshold data, an olfactophore model was constructed that rationalizes the observed odor intensities, and indicates an aliphatic hydrophobe at a distance of 6.3 Å from the centre of the aromatic‐ring binding site. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Recent Advances in the Total Synthesis of Piperidine and Pyrrolidine Natural Alkaloids with Ring‐Closing Metathesis as a Key Step
Authors: Felpin François‐Xavier , Lebreton Jacques
Published: September 2003

This microreview focuses on recent applications of the ring‐closing metathesis reaction (RCM) to construct piperidine and pyrrolidine cores for the total synthesis of natural alkaloids. The most recent examples are described, from simple piperidine alkaloids to complex pentacyclic structures such as (+)‐tabersonine. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Unusual Stabilization of 1,2‐Diamino Derivatives of Quincorine and Quincoridine by Carbon Dioxide: Persistent Crystalline prim‐Ammonium‐Carbamate Salts and Their Reactivity towards Isatoic Acid Anhydride
Authors: Neda Ion , Kaukorat Thomas , Fischer Axel K.
Published: September 2003

The reaction of N‐methylisatoic anhydride 1 with a series of quincorine (QCI) and quincoridine (QCD) derivatives furnished the corresponding QCI‐ and QCD‐substituted anthranilic acid amides 4−9. In the synthesis of 4−9, we investigated the influence of the C5 substituent of 2‐aminomethyl derivatives of QCI and QCD on their basicity and polarity and, therefore, on their reactivity towards isatoic acid anhydride. By exposing a number of 2‐aminomethyl derivatives of QCI and QCD to (carbon dioxide from) air, the formation of carbon dioxide adducts 10−15 was observed. In an unusual reaction, we obtained the first set of chiral ammonium carbamates derived from primary amines, which provides a convenient method for purifying and stabilizing aminomethyl derivatives of QCI and QCD. All compounds were fully characterized by spectroscopic methods. In addition, the structure of 11 was proved by X‐ray crystal structure determination. The heterocyclic nitrogen atoms display trigonal‐pyramidal coordination geometries; the amido group is essentially planar. N‐2′ of the ammonium ion is a triple hydrogen bond donor to the carboxylato oxygen atoms of three different carbamate anions. The resulting net effect is a hydrophilic plane parallel to the ab plane. The crystal packing involves six classical hydrogen bonds. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Reinvestigation into the Synthesis of Oligonucleotides Containing 5‐(β‐D‐Glucopyranosyloxymethyl)‐2′‐deoxyuridine
Authors: Turner John J. , Meeuwenoord Nico J. , Rood Anita , Borst Piet , van der Marel Gijs A. , van Boom Jacques H.
Published: September 2003

A reinvestigation into the synthesis of oligonucleotides containing 5‐(β‐D‐glucopyranosyloxymethyl)‐2′‐deoxyuridine revealed that existing procedures for the preparation of these DNA fragments suffered from decomposition at the final deprotection step. The decomposition product was identified as the corresponding 5‐(aminomethyl)‐2′deoxyuridyl derivative arising from amino substitution of the β‐D‐glucosyl moiety during ammonolysis. This was shown to be suppressed by the use of phosphoramidite 21 in place of 12 for solid‐phase oligonucleotide synthesis, in conjunction with short ammonia treatment at room temperature. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Tele vs. Oxidative Substitution of Hydrogen in meta Monochloromethyl, Dichloromethyl, and Trichloromethyl Nitrobenzenes in the Reaction with Grignard Reagents
Authors: Mąkosza Mieczysław , Varvounis George , Surowiec Marek , Giannopoulo Thomas
Published: September 2003

Grignard reagents add to nitrobenzene derivatives containing trichloromethyl, dichloromethyl, and monochloromethyl groups in the meta position to form σH adducts, which are either further converted through departure of a chloride anion, giving products of tele substitution, or oxidized to products of oxidative nucleophilic substitution of hydrogen. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Side‐Chain Retention During Lithiation of 4‐Picoline and 3,4‐Lutidine: Easy Access to Molecular Diversity in Pyridine Series
Authors: Kaminski Thomas , Gros Philippe , Fort Yves
Published: September 2003

The first direct ring‐selective lithiation of 4‐picoline and 3,4‐lutidine has been achieved through the use of BuLi/LiDMAE aggregates to prevent the usual side‐chain metallation. Several functionalities have been introduced at the C‐2, C‐6 and C‐5 positions by ring‐selective sequential lithiation, opening a simple and fast route to polysubstituted pyridine building blocks. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Condensation Reaction Between α‐Amino Acid Phenylhydrazides and Carbonyl Compounds
Authors: Verardo Giancarlo , Geatti Paola , Martinuzzi Paolo , Merli Marcello , Toniutti Nicoletta
Published: September 2003

The natural α‐amino acid phenylhydrazides 1a−d readily react with the aldehydes 2a−d and ketones 2e−h to produce the 3‐(phenylamino)imidazolidin‐4‐one derivatives 4 in good yields. Their structures were confirmed by X‐ray structural analysis. Polycyclic systems were obtained from the reaction of L‐tryptophan phenylhydrazide (1d) and L‐histidine phenylhydrazide (1e) with benzaldehyde (2c), which gave 1,10‐diphenyl‐2‐(phenylamino)‐2,9,10a‐triazacyclopenta[b]fluoren‐3‐one (5dc) and 4,6‐diphenyl‐7‐(phenylamino)‐3,4,6,7,8a,9‐hexahydro‐8H‐diimidazo[1,5‐a:4′,5′‐d]pyridin‐8‐one (5ec), respectively. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
NMR and X‐ray Crystallographic Analysis of Thermodynamically Stable Tetraphenylporphyrin‐Stoppered Rotaxanes
Authors: Ikeda Taichi , Asakawa Masumi , Goto Midori , Nagawa Yoshinobu , Shimizu Toshimi
Published: September 2003

Tetraphenylporphyrin‐stoppered rotaxanes, in which tetraphenylporphyrin rhodium(III) chloride serves for end‐capping of the thread molecule through axial coordination, were prepared from the inclusion complexes formed between crown ether and secondary ammonium cation derivatives. Two types of the thread molecules, with different molecular lengths, were used for the rotaxane preparation. The obtained porphyrin‐stoppered rotaxanes proved to be thermodynamically stable in their pure forms at room temperature. 1H NMR measurements indicated that the protons of the thread molecule and the crown ether are considerably affected by the shielding effect of the terminal porphyrin. We confirmed that the intensity of the shielding effect is applicable as a probe for estimation of the location of the crown ether. We found different chemical shifts for individual members of pairs of methylene protons on the same crown ether carbon when the relatively shorter thread molecule was used, whereas we observed similar chemical shifts for those in the rotaxane with longer thread molecule. This result indicates that the stronger shielding effect of the porphyrin exposes the two faces of the crown ether to different magnetic environments in the case of the relatively shorter thread molecule. X‐ray crystallography for the porphyrin‐stoppered rotaxane with the relatively shorter thread molecule revealed that the crown ether forms many hydrogen bonds with the thread molecule. We confirmed that not only the hydrogen atoms of the secondary ammonium ion and the neighboring methylene groups, but also the β‐hydrogen atoms of the axially coordinated pyridine moiety participate in hydrogen bond formation with the crown ether oxygen atoms. It is likely that the catechol rings of the crown ether interact with the phenyl groups of the terminal porphyrin. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Sulfene−Pyridine Adducts: Lewis Acid/Base Complexes, Ylides, Pyridinium Sulfinate Zwitterions, or Carbene Ylide/SO2 Complexes?
Authors: Bucher Götz
Published: September 2003

The reactions between a number of sulfenes and pyridine have been investigated by both density functional and ab initio theory. Two reaction channels were found. Addition of pyridine to the sulfene S atom produces products with the character of Lewis acid/base adducts. In polar solvents such as acetonitrile, scipcm calculations predict a shortening of the S−N bond with increasing ylide character, as revealed by long‐wavelength absorptions predicted by time‐dependent DFT calculations. Addition of pyridine to the sulfene C atom affords adducts better described as Lewis acid/base adducts between carbene pyridine ylides and SO2 rather than as pyridinium sulfinate zwitterions. Again, scipcm calculations predict tighter binding in polar solvents. In the series of sulfene‐pyridine adducts investigated, the C‐bound adduct was consistently lower in energy than the S‐bound adduct, by at least 15 kcal/mol. For the formation of the C‐bound adducts an activation enthalpy of 14 kcal/mol or larger is calculated, while the formation of S‐bound sulfene−pyridine adducts is predicted to proceed without any barrier. The S‐bound adducts are therefore formed in kinetically controlled reactions, while the C‐bound adducts are the thermodynamically favored products. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Bismuth Triflate: An Efficient Catalyst for the Formation and Deprotection of Tetrahydropyranyl Ethers
Authors: Stephens Jacqueline R. , Butler Phillip L. , Clow Curtis H. , Oswald Matthew C. , Smith Russell C. , Mohan Ram S.
Published: September 2003

The tetrahydropyranylation of alcohols under solvent‐free conditions is efficiently catalyzed by bismuth triflate (0.1 mol %). The experimental procedure is simple and works well with a variety of alcohols and phenols. The catalyst is insensitive to air and small amounts of moisture, easy to handle and relatively nontoxic. The deprotection of THP ethers is also catalyzed by bismuth triflate (1.0 mol %). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Functionalization of [60]Fullerene and of [60]Fullerene Monoadducts by Photochemical Cycloaddition of 4‐Methyl‐1,2,4‐triazoline‐3,5‐dione
Authors: Ulmer Lars , Siedschlag Christina , Mattay Jochen
Published: September 2003

The photoreactions of 4‐methyl‐1,2,4‐triazoline‐3,5‐dione (NMTAD) with C60 and with several fullerene derivatives have been studied. In general, NMTAD cycloadds to C60 and to its monoadducts with closed structures in a highly regioselective [2+2] fashion at a cis‐1 [6,6] double bond. Cycloadditions to azafulleroids occur by a slightly different pathway and result in partially cluster‐opened bis(adducts). 1,6‐Methano[60]fulleroid, however, also undergoes a [2+2+2] cycloaddition in the absence of light. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
First Isolation of Thione‐Propiolic Acid Adducts − Synthesis of Thiodioxenones
Authors: Okuma Kentaro , Maekawa Shinobu , Shibata Shinji , Shioji Kosei , Inoue Thoru , Kurisaki Tsutomu , Wakita Hisanobu , Yokomori Yoshinobu
Published: September 2003

Treatment of adamantane‐2‐thione (1a) with propiolic acid (2a) afforded a novel type of cycloadduct, spiro[adamantane‐2,2′‐[1,3]oxathiin]‐6‐one (3a), in quantitative yield. The reaction proceeds through a concerted process, as was confirmed by kinetic analysis. Treatment of 1a with butynoic acid or phenylpropiolic acid gave the corresponding adducts regioselectively. Interestingly, only one isomer was obtained by treatment of thiofenchone with propiolic acid, suggesting that the reaction proceeded stereospecifically. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Quantitative Four‐State Conformational Analysis by Ring Current NMR Anisotropy: A Family of Molecules Capable of Intramolecular π‐Stacking
Authors: Chen Jing , Cammers‐Goodwin Arthur
Published: September 2003

A novel, multi‐state, conformational analysis based on the magnetic anisotropy of molecules undergoing fast dynamic exchange is described. Calculated chemical shift tensors combined with experimental data from proton NMR studies were used to quantify conformational distributions as a function of solvent and temperature for a hydrocarbon and two fluorocarbon derivatives of N,N′‐[1,3‐phenylenebis(methylene)]bis(2‐phenylpyridinium) dibromide. Inspection for adequate analyses involved confirming that the mathematical expressions conserved magnetization (mass). Enthalpic parameters from VT‐NMR gave some indication of the nature of the impact of solvent on conformation. Results indicated that electrostatic interactions between aromatic rings can strongly impact organic conformation in solution. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Enantioselective Strecker Reactions between Aldimines and Trimethylsilyl Cyanide Promoted by Chiral N,N′‐Dioxides
Authors: Jiao Zhigang , Feng Xiaoming , Liu Bo , Chen Fuxue , Zhang Guolin , Jiang Yaozhong
Published: September 2003

Axially chiral N,N′‐dioxide Lewis base promoters have been developed and have for the first time been applied to the asymmetric synthesis of α‐amino nitriles through cyanide addition to aldimines. The chiral 3,3′‐dimethyl‐2,2′‐biquinoline N,N′‐dioxide 2 exhibited high enantioselectivity for asymmetric Strecker reactions between N‐benzhydrylimines and trimethylsilyl cyanide. In the presence of 1 equiv. of chiral promoter 2, the cyanosilylation of aldimines afforded the corresponding α‐amino nitriles with ee values of up to 95%. Optically pure products (99% ee) were obtained simply by recrystallization in the cases of some of the products. Moreover, the promoter 2 could be recovered and reused at least four times without any loss of enantioselectivity and reactivity. A putative mechanism for the enantioselective Strecker reactions is also discussed. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
The Combination of TsNH2 and NCS as Nitrogen and Chlorine Sources for Direct Diamination of Enones
Authors: Timmons Cody , Chen Dianjun , Xu Xin , Li Guigen
Published: September 2003

The regio‐, stereo‐, and chemoselective diamination of enones has been achieved without the observation of any haloamines. The reaction employs the readily available inexpensive combination of NCS and TsNH2 as an electrophilic nitrogen source, and three nitriles as nucleophilic nitrogen sources. A novel mechanism involving the formation of aziridinium intermediates from the reaction of TsNHCl with olefins and a new [2+3] cyclic addition for aziridinim ring opening has been proposed for the electrophilic diamination of olefins. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
New 4′‐Functionalized 2,2′:6′,2′′‐Terpyridines for Applications in Macromolecular Chemistry and Nanoscience
Authors: Andres Philip R. , Lunkwitz Ralph , Pabst Gunther R. , Böhn Karlheinz , Wouters Daan , Schmatloch Stefan , Schubert Ulrich S.
Published: September 2003

The well‐known reaction of 4′‐chloro‐2,2′:6′,2′′‐terpyridine with alkoxide nucleophiles leads to 4′‐functionalized 2,2′:6′,2′′‐terpyridines. This reaction allows the easy introduction of different functional groups onto the terpyridine at the 4′‐position, i.e. opposite to the metal binding site, in one reaction step. Among the functionalized 2,2′:6′,2′′‐terpyridines reported here are amines (including chiral examples), carboxylic acids, simple alkoxy‐chain terpyridines with different chain lengths, and a stilbene‐functionalized terpyridine. Moreover, the synthesis of two important already known substances was significantly improved. One example of a sequential functionalization of the (aminopentoxy)terpyridine with a dithiolane functionality is also reported. For two of the alkyl‐chain‐functionalized terpyridines, single‐crystal X‐ray crystallographic data were obtained. Finally, ordered monolayers of alkyl‐substituted terpyridines on HOPG were visualized using STM. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Regio‐ and Stereoselective Dirhodium(II)‐Catalysed Intramolecular C−H Insertion Reactions of α‐Diazo‐α‐(dialkoxyphosphoryl)acetamides and ‐acetates
Authors: Gois Pedro M. P. , Afonso Carlos A. M.
Published: September 2003

α‐Diazo‐α‐(dialkoxyphosphoryl)acetates and ‐acetamides afforded α‐(dialkoxyphosphoryl)lactones and lactams, respectively, in moderate to high yields through dirhodium(II)‐catalysed intramolecular carbon−hydrogen insertion reactions. In the case of α‐diazo‐α‐(dialkoxyphosphoryl)acetamides a remarkable preference for the formation of γ‐lactam was observed, with stereocontrol in favour of the trans diastereomer. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Acidity of Substituted Benzenes − An Ab Initio Study of the Influence of Methoxy, Trifluoromethyl and Trifluoromethoxy Groups by a Novel Trichotomy Formula
Authors: Kovačević Borislav , Maksić Zvonimir B. , Primorac Miljenko
Published: September 2003

The acidities of mono‐ and polysubstituted benzenes incorporating one, two, or three OCH3, OCF3, or CF3 groups were investigated by use of reliable ab initio theoretical models. The calculated deprotonation energies are in very good agreement with available experimental data, although these are unfortunately sparse. A recently developed novel trichotomy formula proved useful for interpretation of predicted variation in acidity in the monosubstituted compounds. In particular, the long‐range final state effect in OCF3 and CF3 derivatives is confirmed. It is reflected in the stabilization of the lone‐pair electrons formed upon deprotonation at the meta and para positions. The theoretically established long‐range influence of OCF3 and CF3 substituents is in accordance with empirical knowledge obtained by experimental chemical reactivity studies. The acidities of multiply substituted benzenes exhibit additivity properties based on the ISA (independent substituent approximation) model established earlier. It is conclusively shown that the combination of the additivity rule and the trichotomy formula offers a powerful tool for interpretation of the acidity of polysubstituted benzenes and of other multiply substituted aromatics, thus shedding new light on this very old and important problem. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Cover Picture: Conception, Characterization and Correlation of New Marine Odorants (Eur. J. Org. Chem. 19/2003)
Authors: Kraft Philip , Eichenberger Walter
Published: September 2003

The cover picture shows, in front of a water surface and with an electon‐density cloud in the form of a water droplet, the best marine odorant of a series of substituted benzo[b][1,4]dioxepinones and 2,3‐dihydro‐1H‐5,9‐dioxacyclohepta[f]indenones. It posseses a very intense and diffusive, marine odor with floral‐aldehydic nuances and an exceptionally low odor threshold of 0.014 ng/L air! A beam highlights the hydrophobic binding centre 6.3 Å apart from the aromatic ring binding site. This feature accounts for its exceptional odor characteristics as was rationalized by an olfactophore model constructed on the basis of 20 measured odor thresholds. A synthetic sequence consisting of PPA‐mediated Friedel−Crafts acylation, Clemmensen reduction, demethylation, Williamson ether synthesis employing 1‐chloro‐2‐(chloromethyl)prop‐1‐ene and subsequent ruthenium tetroxide oxidation opens up a simple, straightforward access to these marine odorants and related structures. Details are discussed in the article by P. Kraft and W. Eichenberger on p. 3735 ff.
Numerical computation of three‐dimensional incompressible Navier–Stokes equations in primitive variable form by DQ method
Authors: Shu C. , Wang L. , Chew Y. T.
Published: September 2003

In this paper, the global method of differential quadrature (DQ) is applied to solve three‐dimensional Navier–Stokes equations in primitive variable form on a non‐staggered grid. Two numerical approaches were proposed in this work, which are based on the pressure correction process with DQ discretization. The essence in these approaches is the requirement that the continuity equation must be satisfied on the boundary. Meanwhile, suitable boundary condition for pressure correction equation was recommended. Through a test problem of three‐dimensional driven cavity flow, the performance of two approaches was comparatively studied in terms of the accuracy. The numerical results were obtained for Reynolds numbers of 100, 200, 400 and 1000. The present results were compared well with available data in the literature. In this work, the grid‐dependence study was done, and the benchmark solutions for the velocity profiles along the vertical and horizontal centrelines were given. Copyright © 2003 John Wiley & Sons, Ltd.
Computation of turbulent free‐surface flows around modern ships
Authors: Li Tingqiu
Published: September 2003

This paper presents the calculated results for three classes of typical modern ships in modelling of ship‐generated waves. Simulations of turbulent free‐surface flows around ships are performed in a numerical water tank, based on the FINFLO‐RANS SHIP solver developed at Helsinki University of Technology. The Reynolds‐averaged Navier–Stokes (RANS) equations with the artificial compressibility and the non‐linear free‐surface boundary conditions are discretized by means of a cell‐centred finite‐volume scheme. The convergence performance is improved with the multigrid method. A free surface is tracked using a moving mesh technology, in which the non‐linear free‐surface boundary conditions are given on the actual location of the free surface. Test cases recommended are a container ship, a US Navy combatant and a tanker. The calculated results are compared with the experimental data available in the literature in terms of the wave profiles, wave pattern, and turbulent flow fields for two turbulence models, Chien's low Reynolds number k–εmodel and Baldwin–Lomax's model. Furthermore, the convergence performance, the grid refinement study and the effect of turbulence models on the waves have been investigated. Additionally, comparison of two types of the dynamic free‐surface boundary conditions is made. Copyright © 2003 John Wiley& Sons, Ltd.
Modelling solitons under the hydrostatic and Boussinesq approximations
Authors: Daily Chris , Imberger Jorg
Published: September 2003

An examination of solitary waves in 3D, time‐dependant hydrostatic and Boussinesq numerical models is presented. It is shown that waves in these models will deform and that only the acceleration term in the vertical momentum equation need be included to correct the wave propagation. Modelling of solitary waves propagating near the surface of a small to medium body of water, such as a lake, are used to illustrate the results. The results are also compared with experiments performed by other authors. Then as an improvement, an alternative numerical scheme is used which includes only the vertical acceleration term. Effects of horizontal and vertical diffusion on soliton wave structure is also discussed. Copyright © 2003 John Wiley & Sons, Ltd.
An implicit edge‐based ALE method for the incompressible Navier–Stokes equations
Authors: Smith Richard W. , Wright Jeffrey A.
Published: September 2003

A new finite volume method for the incompressible Navier–Stokes equations, expressed in arbitrary Lagrangian–Eulerian (ALE) form, is presented. The method uses a staggered storage arrangement for the pressure and velocity variables and adopts an edge‐based data structure and assembly procedure which is valid for arbitrary n‐sided polygonal meshes. Edge formulas are presented for assembling the ALE form of the momentum and pressure equations. An implicit multi‐stage time integrator is constructed that is geometrically conservative to the precision of the arithmetic used in the computation. The method is shown to be second‐order‐accurate in time and space for general time‐dependent polygonal meshes. The method is first evaluated using several well‐known unsteady incompressible Navier–Stokes problems before being applied to a periodically forced aeroelastic problem and a transient free surface problem. Published in 2003 by John Wiley & Sons, Ltd.
A block‐implicit numerical procedure for simulation of buoyant swirling flows in a model furnace
Authors: de Lemos Marcelo J. S.
Published: September 2003

This work reports numerical results for the case of incompressible laminar heated flow with a swirl in a vertical cylindrical chamber. Computations are obtained with a point‐wise block‐implicit scheme. Flow governing equations are written in terms of the so‐called primitive variables and are recast into a general form. The discretized momentum equations are applied to each cell face and then, together with the mass‐continuity, tangential velocity and energy equations, are solved directly in each computational node. The effects of Rayleigh, Reynolds and Swirl numbers on the temperature field are discussed. Flow pattern and scalar residual history are reported. Further, it is expected that more advanced parallel computer architectures can benefit from the error smoothing operator here described. Copyright © 2003 John Wiley & Sons, Ltd.
3D free‐surface flow computation using a RANSE/Fourier–Kochin coupling
Authors: Guillerm Pierre‐Emmanuel , Alessandrini Bertrand
Published: September 2003

A coupling method for numerical calculations of steady free‐surface flows around a body is presented. The fluid domain in the neighbourhood of the hull is divided into two overlapping zones. Viscous effects are taken in account near the hull using Reynolds‐averaged Navier–Stokes equations (RANSE), whereas potential flow provides the flow away from the hull. In the internal domain, RANSE are solved by a fully coupled velocity, pressure and free‐surface elevation method. In the external domain, potential‐flow theory with linearized free‐surface condition is used to provide boundary conditions to the RANSE solver. The Fourier–Kochin method based on the Fourier–Kochin formulation, which defines the velocity field in a potential‐flow region in terms of the velocity distribution at a boundary surface, is used for that purpose. Moreover, the free‐surface Green function satisfying this linearized free‐surface condition is used. Calculations have been successfully performed for steady ship‐waves past a serie 60 and then have demonstrated abilities of the present coupling algorithm. Copyright © 2003 John Wiley & Sons, Ltd.
A deconvolution‐based fourth‐order finite volume method for incompressible flows on non‐uniform grids
Authors: Iannelli P. , Denaro F. M. , Stefano G. De
Published: September 2003

This paper is concerned with the development of a new high‐order finite volume method for the numerical simulation of highly convective unsteady incompressible flows on non‐uniform grids. Specifically, both a high‐order fluxes integration and the implicit deconvolution of the volume‐averaged field are considered. This way, the numerical solution effectively stands for a fourth‐order approximation of the point‐wise one. Moreover, the procedure is developed in the framework of a projection method for the pressure–velocity decoupling, while originally deriving proper high‐order intermediate boundary conditions. The entire numerical procedure is discussed in detail, giving particular attention to the consistent discretization of the deconvolution operation. The present method is also cast in the framework of approximate deconvolution modelling for large‐eddy simulation. The overall high accuracy of the method, both in time and space, is demonstrated. Finally, as a model of real flow computation, a two‐dimensional time‐evolving mixing layer is simulated, with and without sub‐grid scales modelling. Copyright © 2003 John Wiley & Sons, Ltd.
Characteristic Euler shock‐fitting formulation for multi‐dimensional flows
Authors: Basesme Ertugrul A. , Akmandor I. Sinan , Ucer Ahmet S.
Published: September 2003

A three‐dimensional explicit time marching algorithm has been developed for the numerical solution of inviscid internal flows. The formulation uses the natural streamline co‐ordinate system. The unsteady Euler equations in non‐conservative form are expressed in terms of the extended Riemann variables and the flow angles. Along the characteristic trajectories in the space–time domain, these equations reduce to a system of ordinary differential equations. Boundary conditions are also implemented in characteristic form. Shock waves are calculated after performing a one‐point shock correction that maintains conservation across the discontinuity. The algorithm has been applied to subsonic, transonic and supersonic test cases. Despite the wide range in the Mach number and the diversity of the tested flow geometries, close agreement have been obtained with available analytical and numerical results. Copyright © 2003 John Wiley & Sons, Ltd.
Somatosensory areas engaged during discrimination of steady pressure, spring strength, and kinesthesia
Authors: Bodegård Anna , Geyer Stefan , Herath Priyantha , Grefkes Christian , Zilles Karl , Roland Per E.
Published: September 2003

The aim of this study was to locate neuronal populations in the somatosensory areas engaged during discrimination of differences in: (1) static sustained pressure on the distal phalanx (PRESS); (2) spring strengths (SSTIFF) during active flexion of the right index finger; and (3) the change in position of a limb with contracting muscles, i.e., kinesthesia (KIN), during active flexion of the right index finger. The stimuli used were spring‐loaded cylinders. The regional cerebral blood flow (rCBF) was measured with positron emission tomography (PET). The active fields were related to cytoarchitectonic areas of the somatosensory cortex (areas 3a, 3b, 1, and 2) and the primary motor cortex (areas 4a and 4p). We hypothesized that SSTIFF and KIN would activate areas 3a and 2. All three conditions, when contrasted against a rest condition, activated cytoarchitectural areas 3b, 1, and 2, and presumptive somatosensory areas in the left parietal operculum and right supramarginal gyrus in accordance with these areas receiving information from cutaneous mechanoreceptive afferents. Area 3a was only activated in SSTIFF and KIN, consistent with observations in monkeys and cats, showing that afferents from muscle receptors project to area 3a, and indicating that a similar arrangement seems to be apparent in humans. SSTIFF and KIN activated the right anterior lobe of the cerebellum, the left area 4a and left area 2 more than did PRESS, likely due to a combination of active movements and muscle receptor feed‐back. Hum. Brain Mapp. 20:103–115, 2003. © 2003 Wiley‐Liss, Inc.
Modeling intra‐subject correlation among repeated scans in positron emission tomography (PET) neuroimaging data
Authors: Bowman F. DuBois , Kilts Clinton
Published: September 2003

Many in vivo positron emission tomography (PET) neuroimaging studies record correlates of regional cerebral blood flow (rCBF) in a series of scans for each individual, usually under different experimental conditions. Typical methods for statistical analysis involve fitting voxel‐specific general linear models (GLM) that assume spherical normal errors, implying that all voxel‐specific rCBF measurements are independent and arise from identical normal probability distributions. While the spherical GLM provides a unified and computationally efficient approach to estimation, the likely correlations among an individual's repeated scans and heteroscedasticity between conditions prompt the use of extended statistical methodology. We outline a more general method to analyze PET data using random effects and correlated errors to model unequal variances across conditions as well as covariances (correlations) among the repeated scans for each individual. We introduce correlation maps to display intra‐subject correlations between an individual's rCBF measurements from different scans. We illustrate the application of our model using data from a study of social anxiety and highlight analytical advantages over the spherical GLM. Hum. Brain Mapping 20:59–70, 2003. © 2003 Wiley‐Liss, Inc.
Dopamine D2 receptors and transporters in type 1 and 2 alcoholics measured with human whole hemisphere autoradiography
Authors: Tupala Erkki , Hall Håkan , Bergström Kim , Mantere Tuija , Räsänen Pirkko , Särkioja Terttu , Tiihonen Jari
Published: September 2003

Increasing evidence implies the involvement of the dopamine (DA) system in the pathogenesis of alcoholism. We measured striatal DA D2 receptors in Cloninger type 1 and 2 alcoholics by using [125I]epidepride in human postmortem whole hemispheric autoradiography (WHA), which provides high‐resolution images corresponding to positron emission tomographic (PET) studies. We also evaluated the correlation between transporter and receptor DA binding site densities and putative correlation of [125I]epidepride binding between the dorsal striatum and nucleus accumbens. In the type 1 alcoholics, the DA D2 receptor density was 21.4–32.6% lower in all dorsal striatal structures (caudate, putamen, globus pallidus) when compared with the controls. Type 2 alcoholics had 19.6–21.4% lower binding in other dorsal striatal structures, except medial globus pallidus, where they were not significantly different from controls. The density of DA D2 receptors and DAT had a significant positive correlation only in the putamen of type 1 alcoholics. The binding of [125I]epidepride showed also consistent and statistically significant positive correlation between nucleus accumbens and all dorsal striatal areas in type 1 alcoholics but not in the controls. In the type 2 alcoholics, the correlation was weaker than that observed in the type 1 alcoholics, and no correlation was observed between nucleus accumbens and globus pallidus. Our results show that these two subgroups of alcoholics have stark differences in their DA D2 receptor binding characteristics. Type 2 alcoholics may have selective deficiency in the dorsal striatum, whereas in limbic structures they may not differ significantly from controls. Moreover, WHA provides a useful tool for detailed mapping of neuronal receptors in healthy as well as diseased brain, and can also be used in radioligand development for PET. Hum. Brain Mapp. 20:91–102, 2003. © 2003 Wiley‐Liss, Inc.