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1.
《Bioorganic & medicinal chemistry》2016,24(8):1619-1636
A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pKi = 8.4, DA D2 pKi = 6.0 and hERG fpKi = 5.2) showed a balanced profile and further refinements are in progress around this molecule. 相似文献
2.
《Journal of electromyography and kinesiology》2014,24(6):780-788
In addition to the role of muscle coactivation, a major question in the field is how antagonist activation is controlled to minimize its opposing effect on agonist muscle performance. Muscle fatigue is an interesting condition to analyze the neural adjustments in antagonist muscle activity and to gain more insights into the control mechanisms of coactivation. In that context, previous studies have reported that although the EMG activity of agonists and antagonists increase in parallel, the ratio between EMG activities in the two sets of muscles during a fatiguing submaximal contraction decreased progressively and contributed to a reduction in the time to task failure. In contrast, more recent studies using a novel normalization procedure indicated that the agonist/antagonist ratio remained relatively constant, suggesting that the fatigue-related increase in coactivation does not impede performance. Current knowledge also indicates that peripheral mechanisms cannot by themselves mediate the intensity of antagonist coactivation during fatiguing contractions, implying that supraspinal mechanisms are involved. The unique modulation of the synaptic input from Ia afferents to the antagonist motor neurones during a fatiguing contraction of the agonist muscles further suggests a separate control of the two sets of muscles. 相似文献
3.
《Bioorganic & medicinal chemistry letters》2014,24(15):3385-3388
5-Oxo-ETE is the most potent eosinophil chemoattractant among lipid mediators. We have developed two 5-oxo-ETE receptor antagonists. In the course of the work, we have developed a procedure to selectively introduce a cis and trans double bond in an alkyl side chain. Reacting indolecarboxaldehydes with alkyl ylides using the Li base affords the trans olefins, whereas using the K base yields the cis olefins. 相似文献
4.
Rambabu Dakarapu Ramu Errabelli Vijaya L. Manthati Adeniyi Michael Adebesin Deb K. Barma Deepan Barma Victor Garcia Fan Zhang Michal Laniado Schwartzman John R. Falck 《Bioorganic & medicinal chemistry letters》2019,29(19):126616
19-Hydroxyeicosatetraenoic acid (19-HETE, 1), a metabolically and chemically labile cytochrome P450 eicosanoid, has diverse biological activities including antagonism of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE, 2). A SAR study was conducted to develop robust analogs of 1 with improved in vitro and in vivo efficacy. Analogs were screened in vitro for inhibition of 20-HETE-induced sensitization of rat renal preglomerular microvessels toward phenylephrine and demonstrated to normalize the blood pressure of male Cyp4a14(-/-) mice that display androgen-driven, 20-HETE-dependent hypertension. 相似文献
5.
Samarjit Patnaik Dipanwita Basu Noel Southall Seameen Dehdashti Kanny K. Wan Wei Zheng Marc Ferrer Mercedes Taylor Daniel A. Engel Juan Jose Marugan 《Bioorganic & medicinal chemistry letters》2019,29(9):1113-1119
Nonstructural protein 1 (NS1) plays a crucial function in the replication, spread, and pathogenesis of influenza virus by inhibiting the host innate immune response. Here we report the discovery and optimization of novel pyrazolopyridine NS1 antagonists that can potently inhibit influenza A/PR/8/34 replication in MDCK cells, rescue MDCK cells from cytopathic effects of seasonal influenza A strains, reverse NS1-dependent inhibition of IFN-β gene expression, and suppress the slow growth phenotype in NS1-expressing yeast. These pyrazolopyridines will enable researchers to investigate NS1 function during infection and how antagonists can be utilized in the next generation of treatments for influenza infection. 相似文献
6.
Mohamad Wessam Alnouri Stephan Jepards Alessandro Casari Anke C. Schiedel Sonja Hinz Christa E. Müller 《Purinergic signalling》2015,11(3):389-407
Adenosine receptors (ARs) have emerged as new drug targets. The majority of data on affinity/potency and selectivity of AR ligands described in the literature has been obtained for the human species. However, preclinical studies are mostly performed in mouse or rat, and standard AR agonists and antagonists are frequently used for studies in rodents without knowing their selectivity in the investigated species. In the present study, we selected a set of frequently used standard AR ligands, 8 agonists and 16 antagonists, and investigated them in radioligand binding studies at all four AR subtypes, A1, A2A, A2B, and A3, of three species, human, rat, and mouse. Recommended, selective agonists include CCPA (for A1AR of rat and mouse), CGS-21680 (for A2A AR of rat), and Cl-IB-MECA (for A3AR of all three species). The functionally selective partial A2B agonist BAY60-6583 was found to additionally bind to A1 and A3AR and act as an antagonist at both receptor subtypes. The antagonists PSB-36 (A1), preladenant (A2A), and PSB-603 (A2B) displayed high selectivity in all three investigated species. MRS-1523 acts as a selective A3AR antagonist in human and rat, but is only moderately selective in mouse. The comprehensive data presented herein provide a solid basis for selecting suitable AR ligands for biological studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s11302-015-9460-9) contains supplementary material, which is available to authorized users. 相似文献7.
《Bioorganic & medicinal chemistry letters》2020,30(18):127417
Solid preclinical evidence links vasopressin to social behavior in animals, so, extensive work has been initiated to find new vasopressin V1a receptor antagonists which can improve deteriorated social behavior in humans and can treat the core symptoms of autistic behavior, as well. Our aim was to identify new chemical entities with antagonizing effects on vasopressin V1a receptors. Continuing our previous work, we found an in vitro and in vivo orally active V1a selective antagonist molecule (40) among [1,2,4]triazolo[4,3-a][1]benzazepines. 相似文献
8.
The biological control efficacy of single or multiple applications of the mutualistic endophyte Fusarium oxysporum strain 162, the egg pathogen Paecilomyces lilacinus strain 251 and the antagonistic bacteria Bacillus firmus toward Radopholus similis was investigated in pot trials with banana under glasshouse conditions. R. similis was controlled substantially in single and combined applications of F. oxysporum with P. lilacinus or B. firmus. The combination of F. oxysporum and P. lilacinus caused a 68.5% reduction in nematode density whereas the individual applications reduced the density by 27.8% and 54.8% over
the controls, respectively. Combined application of F. oxysporum and B. firmus was the most effective treatment in controlling R. similis on banana (86.2%), followed by B. firmus alone (63.7%). The compatibility of the biocontrol agents, as well the capacity of F. oxysporum to colonize banana roots in the absence or presence of P. lilacinus was also investigated. P. lilacinus did not adversely affect endophytic colonization by F. oxysporum. Biological control of R. similis in banana can therefore be enhanced via combined applications of antagonists with different modes of action that target different
stages in the infection process.
Handling editor: Ralf-Udo Ehlers 相似文献
9.
Satoru Ito Yukari Hirata Yasushi Nagatomi Atsushi Satoh Gentaroh Suzuki Toshifumi Kimura Akio Satow Shunsuke Maehara Hirohiko Hikichi Mikiko Hata Hisashi Ohta Hiroshi Kawamoto 《Bioorganic & medicinal chemistry letters》2009,19(18):5310-5313
We describe here the discovery and biological profile of a series of isoindolinone derivatives as developed mGluR1 antagonists. Our combined strategy of rapid parallel synthesis and conventional medicinal optimization successfully led to N-cyclopropyl 22 and N-isopropyl isoindolinone analogs 21 and 23 with improved in vivo DMPK profiles. Moreover the most advanced analog 23 showed an oral antipsychotic-like effect at a dose of 1 mg/kg in an animal model. 相似文献
10.
Fabien Vincent Alejandra Acevedo Margaret T. Nguyen Michelle Dourado Jeff DeFalco Amy Gustafson Peter Spiro Daniel E. Emerling Michael G. Kelly Matthew A.J. Duncton 《Biochemical and biophysical research communications》2009,389(3):490-494
TRPV4, a close relative of the vanilloid receptor TRPV1, is activated by diverse modalities such as endogenous lipid ligands, hypotonicity, protein kinases and, possibly, mechanical inputs. While its multiple roles in vivo are being explored with KO mice and selective agonists, there is a dearth of selective antagonists available to examine TRPV4 function. Herein we detail the use of a focused library of commercial compounds in order to identify RN-1747 and RN-1734, a pair of structurally related small molecules endowed with TRPV4 agonist and antagonist properties, respectively. Their activities against human, rat and mouse TRPV4 were characterized using electrophysiology and intracellular calcium influx. Significantly, antagonist RN-1734 was observed to completely inhibit both ligand- and hypotonicity-activated TRPV4. In addition, RN-1734 was found to be selective for TRPV4 in a TRP selectivity panel including TRPV1, TRPV3 and TRPM8, and could thus be a valuable pharmacological probe for TRPV4 studies. 相似文献