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721.
3H-nicotine and 125I-alpha-bungarotoxin-labeled nicotinic receptors in the interpeduncular nucleus of rats. I. Subnuclear distribution 总被引:1,自引:0,他引:1
G S Hamill P B Clarke A Pert D M Jacobowitz 《The Journal of comparative neurology》1986,251(3):398-406
The distribution of nicotinic receptors within the interpeduncular nucleus (IPN) was determined in male rats following in vitro labeling with the cholinergic ligands 3H-nicotine and 125I-alpha-bungarotoxin (BTX). Autoradiographic images of two rostrocaudal levels of IPN were analyzed by computer-assisted densitometry and the optical density contributed by displaceable labeling was determined in the rostral, central, intermediate, and lateral subnuclei. 3H-nicotine labeling density within the four subnuclei differs significantly at both levels of IPN. The greatest density of labeling is localized in the rostral subnucleus, followed in order of diminishing density by the central, intermediate, and lateral subnuclei. Labeling within the rostral subnucleus is prominently localized within its central zone. In the central subnucleus, a dense concentration of binding sites is apparent in the middle region, adjacent to less dense vertically oriented columns; 3H-nicotine binding sites in the lateral subnuclei appear to be most concentrated medially, adjacent to the intermediate subnuclei. 125I-BTX labeling density within the four subnuclei also differs significantly at both levels of IPN. The greatest density of labeling is found in the rostral subnucleus, followed in order of decreasing density by the lateral, central, and intermediate subnuclei. The ovoid regions of the rostral subnucleus contain dense 125I-BTX labeling. In the lateral subnuclei, 125I-BTX binding appears to be predominantly along the lateral margins of the subnucleus. The present data indicate that the IPN contains two distinct populations of putative cholinergic nicotinic receptors identified, respectively, by 3H-nicotine and 125I-BTX labeling. Each population of labeled receptors is uniquely localized in patterns that suggest differences in density within and across subnuclei. 相似文献
722.
The change in benzodiazepine(BZ)-receptor affinity for selected BZ receptor ligands, induced by pentobarbital at 30 degrees C in the presence of 200 mM NaCl (barbiturate shift) was investigated. The affinity for benzodiazepines (e.g. flunitrazepam) was increased approximately two-fold by the presence of pentobarbital (1 mM) whereas the affinity for convulsive BZ-receptor ligands (e.g. DMCM ) was reduced approximately two-fold. The affinity for BZ-receptor antagonists (e.g. Ro 15-1788) was unaltered by pentobarbital. The results obtained suggest that barbiturate shifts have predictive value in determining the pharmacological efficacies of BZ-receptor ligands. However, compounds such as CL 218.872 and ZK 93423 would not have been recognized as agonists, notwithstanding their clear agonistic profile in pharmacological tests. 相似文献
723.
724.
Receptor-selective fluorescent ligands have come into increasing use as scientific tools for the study of receptor physiology and pathophysiology at the cellular and even the subcellular level. Furthermore, they are being increasingly investigated as tools in drug discovery research. In both cases, techniques employing receptor-selective fluorescent ligands have proved to be complementary to, and in several cases even superior to, the traditional-radioligand based techniques. Increasing costs and public concerns associated with radioactive isotope use and dispersal are also making the use of fluoresecent ligands more attractive in research and diagnostic use. With the increasing rate of discovery of new receptors and receptor subtypes and newer more potent and/or selective receptor ligands and drugs, there will be an accompanying need for the design and development of new highly potent and selective fluorescent ligands to aid in the investigation of the physiological and pathophysiological functions of these new receptors and also in the development of drugs acting specifically at these receptors. This review presents a background of development of selected fluorescent ligands, primarily those for small molecule and small peptide based ligands. © 1994 Wiley-Liss, Inc. 相似文献
725.
Stephen G. Holtzman 《Psychopharmacology》1994,116(3):249-254
This study was performed to characterize pharmacologically the discriminative stimulus effects of dextromethorphan, an antitussive that binds with high affinity to a subtype ofsigma site in the brain. Dextrorphan, a metabolite of dextromethorphan, has phencyclidine (PCP)-like effects. Therefore, training was conducted with dextromethorphan injected by the SC route, which minimizes dextrorphan formation compared to the IP route. The training dose used, 30 mg/kg, by the SC route did not occasion selection of the PCP-appropriate choice lever in rats discriminating IP injections of 2.0 mg/kg PCP from saline. (In contrast, by the IP route the ED50 of dextromethorphan for PCP-appropriate lever selection was 21.7 mg/kg). In rats discriminating 30 mg/kg (SC) of dextromethorphan from distilled water, dextromethorphan was slightly more potent SC than it was IP (ED50s for dextromethorphan-appropriate lever selection: 8.5 and 14.9 mg/kg, respectively). These animals generalized dose-dependently and completely to PCP and to other PCP-receptor ligands, but selected the vehicle-appropriate choice lever when tested withsigma-site ligands,mu-opioid agonists, and naltrexone. Concurrent administration of naltrexone orsigma-site ligands with 30 mg/kg dextromethorphan did not block dextromethorphan-appropriate responding. These results show that the discriminative effects of SC dextromethorphan are PCP-like and are not mediated by the high-affinity dextromethorphan binding site or by themu-opioid receptor. Because little dextrorphan is formed when dextromethorphan is given SC and because dextromethorphan itself has low affinity for the PCP receptor, the discriminative effects of SC dextromethorphan probably are mediated by a recognition site related closely to but different from the PCP receptor. 相似文献
726.
Jean E. Olley 《Clinical and experimental pharmacology & physiology》1989,16(6):535-538
1. An introduction to the current knowledge of the mu-, kappa- and delta-opioid receptors will be given. 2. The many problems associated with opiate ligands with respect to selectivity, potency, slow receptor kinetics, instability and poor access to the central nervous system will be discussed. 3. Current systems for analysis of the receptor profile of opiate ligand activity will be given. 4. The properties of opioid ligands will be discussed in the context of the identified problems. 相似文献
727.
Effective, rapid screening of hybridoma supernatants for monoclonal antibodies against the dopaminergic antagonists pimozide and haloperidol, and the serotonergic antagonist kketanserin was performed using a ‘free 3H-ligand’ assay. Anti-mouse Ig-coated microtiter plates were incubated with hybridoma supernatants prior to incubation with excess 3H-ligand. After removal of free 3H-ligand, bound 3H-ligand was eluted with acid for liquid scintillation counting. With minor modification, the assay can be used to screen hybridomas for anti-anti-ligand (anti-idiotypic) antibodies. 相似文献
728.
(-)-14-去甲基石杉碱甲的不对称全合成及其乙酰胆碱酯酶抑制活性老年痴呆症药物石杉碱甲类似物研究VI.(-)-14-去甲基石杉碱甲的不对称全合成及其乙酰胆碱酯酶抑制活性 总被引:2,自引:0,他引:2
目的(-)-14-去甲基石杉碱甲的合成及其抑制乙酰胆碱酯酶活性研究。方法从β-酮酯3与2-亚甲基-1,3-丙二醇双醋酸酯4在手性膦配体钯催化下,对映选择性的形成双环化合物5,双键移位后得到关键中间体6,进而复结晶富集后,得到光学纯6。经Wittig反应,得双键化合物7,酯基水解后,得到相应酸8。经改良的Curtius重排,产生氨基甲酸酯9。除去保护后,得目标化合物2。结果(-)-14-去甲基石杉碱甲仅是天然(-)-石杉碱甲抑制乙酰胆碱酯酶活性1/8。结论由电鳐乙酰胆碱酯酶与(-)-石杉碱甲复合物X-射线衍射结构分析揭示,14-甲基与酶形成氢键是(-)-石杉碱甲高抑制活性的一个必要基团。 相似文献
729.
S. S. Ashraf E. Anderson K. Duke P.T. Hamilton Z. Fredericks 《Chemical biology & drug design》2003,61(5):263-273
Abstract: Phage display is a powerful technology that allows identification of high affinity peptides that bind specifically to a given molecular target. Using a highly complex peptide display library, we have identified separate classes of peptides that bind to protein kinase C alpha (PKCα) only under activation conditions. Furthermore, peptide binding was specific to PKCα and not to any of the other closely related PKC isoforms. The conformational and isoform specificity of the peptide binding was demonstrated using surface plasmon resonance as well as time‐resolved fluorescence assays. Kinase assays showed that these peptides were not direct substrates for PKC nor did they inhibit phosphorylation of PKC substrates. These peptides are most likely directed against protein–protein interaction sites on PKC. The data presented here offers another example of application of phage display technology to identify conformation‐dependent peptide probes against therapeutically important drug targets. These peptides are ideally suited to be used as surrogate ligands to identify compounds that bind specifically to PKCα, as well as conformational probes to detect activated forms of PKCα. 相似文献
730.