全文获取类型
收费全文 | 2238篇 |
免费 | 164篇 |
国内免费 | 78篇 |
专业分类
2480篇 |
出版年
2024年 | 2篇 |
2023年 | 22篇 |
2022年 | 43篇 |
2021年 | 46篇 |
2020年 | 54篇 |
2019年 | 85篇 |
2018年 | 92篇 |
2017年 | 57篇 |
2016年 | 53篇 |
2015年 | 67篇 |
2014年 | 116篇 |
2013年 | 177篇 |
2012年 | 76篇 |
2011年 | 188篇 |
2010年 | 126篇 |
2009年 | 155篇 |
2008年 | 145篇 |
2007年 | 139篇 |
2006年 | 127篇 |
2005年 | 130篇 |
2004年 | 113篇 |
2003年 | 81篇 |
2002年 | 77篇 |
2001年 | 35篇 |
2000年 | 39篇 |
1999年 | 31篇 |
1998年 | 34篇 |
1997年 | 20篇 |
1996年 | 21篇 |
1995年 | 30篇 |
1994年 | 10篇 |
1993年 | 8篇 |
1992年 | 13篇 |
1991年 | 15篇 |
1990年 | 2篇 |
1989年 | 9篇 |
1988年 | 5篇 |
1987年 | 4篇 |
1986年 | 2篇 |
1985年 | 5篇 |
1984年 | 11篇 |
1983年 | 2篇 |
1982年 | 4篇 |
1981年 | 3篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1977年 | 3篇 |
1975年 | 1篇 |
排序方式: 共有2480条查询结果,搜索用时 15 毫秒
1.
(+)-2,9 alpha-Dimethyl-5-(m-hydroxyphenyl)morphan is the only phenylmorphan analog whose affinity for opioid kappa-receptors is greater than its affinity for opioid mu-receptors. Pharmacologically, the compound is a pure opioid antagonist devoid of agonist activity in in vivo assays of antinociception. The absolute configuration of the compound has been determined to be (1R,5S,9R) from an X-ray crystallographic study of the chloride salt. Thus, the absolute configuration corresponds to that of the atypical opioid agonist (-)-phenylmorphan while the weak atypical agonist (-)-2,9 alpha-dimethyl-5-(m- hydroxyphenyl)morphan corresponds to the potent morphine-like (+)-phenylmorphan. The preferred orientations of the phenyl ring for the two stereoisomers were determined using the molecular mechanics program MM2-87 and found to vary from that of the two parent compounds. The atypical properties of the two 9 alpha-methyl analogs is consistent with an opioid ligand model which proposes that morphine-like properties require a particular range of phenyl orientations. There was good agreement between the structure obtained from X-ray crystallography and computed with the MM2-87 program. 相似文献
2.
A computer algorithm, CLIX, capable of searching a crystallographic data-base of small molecules for candidates which have both steric and chemical likelihood of binding a protein of known three-dimensional structure is presented. The algorithm is a significant advance over previous strategies which consider solely steric or chemical requirements for binding. The algorithm is shown to be capable of predicting the correct binding geometry of sialic acid to a mutant influenza-virus hemagglutinin and of proposing a number of potential new ligands to this protein. 相似文献
3.
J.A. David P.J. Crowley S.G. Hall M. Battersby D.B. Sattelle 《Journal of insect physiology》1984,30(3):191-196
The actions of synthetic piperidine derivatives on the response to ionophoretically-applied acetylcholine (ACh) have been tested on the cell body membrane of the fast coxal depressor motoneurone (Ff) of the cockroach Periplaneta americana. The cis form and the cis (80%):trans (20%) mixture of 2-methyl-6-undecyl piperidine were the most effective (the half-maximal blocking action of the mixed isomers was estimated to be 6.3 × 10?5 M). Less potent was the cis (50%):trans (50%) mixture of 2-methyl-6-tridecyl piperidine. However, pure cis 2-methyl-6-tridecyl piperidine was even less effective than the mixed isomers, indicating that, in the case of the tridecyl derivative, the trans form was largely responsible for the block of the ACh response.Cis 2-Methyl-6-undecyl piperidine failed to inhibit the binding of N-[propionyl-3H] propionylated α-bungarotoxin to metathoracic ganglion homogenates at concentrations up to 1.0 × 10?4 M. Also, block of ACh-induced current by 2-methyl-6-undecyl piperidine (cis 80%:trans 20%) was largely independent of membrane potential in the range ?120 mV to ?60 mV, indicating an interaction with the closed ACh receptor/ion channel complex at a site which, in the case of the cis isomer, is separate from the binding site for α-bungarotoxin. 相似文献
4.
Prediction of thermodynamic parameters of protein-protein and antigen-antibody complex formation from high resolution structural parameters has recently received much attention, since an understanding of the contributions of different fundamental processes like hydrophobic interactions, hydrogen bonding, salt bridge formation, solvent reorganization etc. to the overall thermodynamic parameters and their relations with the structural parameters would lead to rational drug design. Using the results of the dissolution of hydrocarbons and other model compounds the changes in heat capacity (Cp), enthalpy (H) and entropy (S) have been empirically correlated with the polar and apolar surface areas buried during the process of protein folding/unfolding and protein-ligand complex formation. In this regard, the polar and apolar surfaces removed from the solvent in a protein-ligand complex have been calculated from the experimentally observed values of changes in heat capacity (Cp) and enthalpy (H) for protein-ligand complexes for which accurate thermodynamic and high resolution structural data are available, and the results have been compared with the x-ray crystallographic observations. Analyses of the available results show poor correlation between the thermodynamic and structural parameters. Probable reasons for this discrepancy are mostly related with the reorganization of water accompanying the reaction which is indeed proven by the analyses of the energetics of the binding of the wheat germ agglutinin to oligosaccharides. 相似文献
5.
Raquel Fernández-Durango José A. de Juan Horatio Zimman Francisco J. Moya Mario Garcia de la Coba Arturo Fernández-Cruz 《Journal of neurochemistry》1994,62(4):1482-1488
Abstract: Specific endothelin (ET) binding sites were characterized in membranes prepared from human cerebral cortices using binding assay and cross-linking analysis. The presence of immunoreactive (IR) ET-1 was studied by radioimmunoassay. Saturation binding experiments revealed that the K D and B max for 125 I-ET-1 and 125 l-ET-3 to membranes from gray matter were 25 ± 6 pM and 115 ± 15 fmol/mg of protein and 24 ± 5 p M and 108 ± 13 fmol/mg of protein, respectively. Similar results were obtained for white matter. In the presence of 10 n M sarafotoxin-6c, which is selective for ETB receptors, 125 I-ET-1 and 125 l-ET-3 binding was totally abolished. However, in the presence of 1 μ M BQ123, which is selective for ETA receptors, both bindings were not affected. These results suggest that the human cerebral cortex contains only ETB receptors. Cross-linking of 125 I-ET-1 and 125 l-ET-3 to membranes with disuccinimidyl suberate resulted in the labeling of two bands of 48 and 31 kDa. Concentrations of IR-ET-1 in the gray and white matter were 7.0 ± 3.2 and 2.5 ± 1.7 fmol/g wet weight, respectively. The demonstration of high-affinity ETB receptors and the presence of IRET-1 suggest that the peptide may act as a neurotransmitter or neuromodulator in the human cerebral cortex. 相似文献
6.
Takeshi Sagara Hiromu Egashira Mikako Okamura Ikuo Fujii Yasuyuki Shimohigashi Ken Kanematsu 《Bioorganic & medicinal chemistry》1996,4(12):2151-2166
For three-dimensional understanding of the mechanisms that control potency and selectivity of the ligand binding at the atomic level, we have analysed opioid receptor-ligand interaction based on the receptor's 3D model. As a first step, we have constructed molecular models for the multiple opioid receptor subtypes using bacteriorhodopsin as a template. The S-activated dihydromorphine derivatives should serve as powerful tools in mapping the three-dimensional structure of the μ opioid receptor, including the nature of the agonist-mediated conformational change that permits G protein-coupling to ‘second messenger’ effector molecules, and in identifying specific ligand-binding contacts with the μ opioid receptor. The analyses of the interactions of some opioid ligands with the predicted ligand binding sites are consistent with the results of the affinity labeling experiments. 相似文献
7.
The complex [Ru(SB12H11)(NH3)5]·2H2O has been prepared by the reaction of Cs2B12H11SH with [RuCl(NH3)5]Cl2 in aqueous solution. The complex represents the first reported example of the borocaptate anion acting as a ligand. The structure of the complex has been determined by single crystal X-ray diffraction analysis. The crystal parameters are monoclinic, space group P21/c, A = 8.056(1), B = 14.240(2), C = 15.172(2) Å, β=98.48° and Z = 4. The ruthenium atom has a distorted octahedral coordination. The distortion is probably due to the high (3−) charge and the large bulk of the borocaptate ligand. These features can also be observed in the spectroscopic properties of the complex. 相似文献
8.
Stereognostic coordination chemistry 4 the design and synthesis of a selective uranyl ion complexant
A new approach to ligand design for the sequestration of metal-oxo cations has been called stereognostic coordination chemistry, in that the ligand incorporates a traditional Lewis base coordination to the metal center and a hydrogen bond donor to interact with the oxo group. This paper reports the synthesis of ligands that are more rigid and sterically predisposed to bind the targeted UO22+ cation. These are the tripod ligands tris-N,N′,N′′-[2-(2-carboxy-phenoxy)ethyl]-1,4,7-triazacyclononane bis-hydrochloride (ETAC · 2HCl) and tris-N,N′,N′′-[2-(2-carboxy-4-decyl-phenoxy)ethyl]-1,4,7-triazacyclononane tris-hydrochloride (DETAC · 3HCl), which chelate uranyl with a tris-carboxylate coordination sphere and provide a hydrogen bond donor through a protonated amine on the triazacyclononane macrocycle to interact with one uranyl oxo atom. Structural models predict that upon uranyl binding the hydrogen bond donor must point directly towards the oxo atom, enforcing a stereognostic interaction. Both ETAC and DETAC chelate the uranyl ion; DETAC is a powerful extractant and will quantitatively extract uranyl into an organic phase at pH 1.9 and above. The extraction coefficient is estimated to be 1014 in neutral aqueous conditions. Vibrational spectra of 18O labeled UO22+ have been used to probe the stereognostic coordination to uranyl utilizing hydrogen bonding. 相似文献
9.
S. K. Dhar 《Inorganica chimica acta》1995,240(1-2):609-614
Cyclic voltammetry at a micro electrode of Co(II) salen, Fe(II) salen, electrode generated Fe(II)(acac)2, Fe(II) (salicylaldehyde)2, Fe(II) (salicylaldoxime)2, Fe(II) (bipy)3, Fe(II) (bipy)2, Co(II) (bipy)3, Co(II) (benzacac)2, and electrode generated Co(acac)2 in oxygen saturated aprotic solvents show positive shift of the O2 sigmoidal wave, as well as enhancement of the limiting current in the case of the first five compounds. In the case of Co(II) (bipy)3 the slope of the sigmoidal wave due to O2 becomes more positive, while for the other two Co(II) complexes there is no change except a small decrease in the wave height. The data are used to correlate and predict the O2 binding properties of the chelates in solution. The data for the diketone complexes of Co(II) indicate absence of any direct association, which is in line with the interpretation offered in the literature on the mechanism of their catalytic role in the O2 oxidation of substrates. The mechanism of the autoxidation of dimethylformamide in the presence of Fe(III) (bipy)3 and Cu(II) (bipy)2 is elucidated by the observation that these higher valent compounds are reduced to their next lower oxidation state by DMF. 相似文献
10.
David W. Deerfield Douglas J. Fox Martin Head-Gordon Richard G. Hiskey Lee G. Pedersen 《Proteins》1995,21(3):244-255
The first coordination shell of an Mg(II) ion in a model protein environment is studied. Complexes containing a model carboxylate, an Mg(II) ion, various ligands (NH3, H2S, imidazole, and formaldehyde) and water of hydration about the divalent metal ion were geometry optimized. We find that for complexes with the same coordination number, the unidentate carboxylate–Mg(II) ion is greater than 10 kcal mol?1 more stable than the bidentate orientation. Imidazole was found to be the most stable ligand, followed in order by NH3 formaldehyde, H2O, and H2S. © 1995 Wiley-Liss, Inc. 相似文献