全文获取类型
收费全文 | 98篇 |
免费 | 10篇 |
出版年
2021年 | 1篇 |
2018年 | 5篇 |
2017年 | 2篇 |
2015年 | 4篇 |
2014年 | 4篇 |
2013年 | 5篇 |
2012年 | 10篇 |
2011年 | 9篇 |
2010年 | 2篇 |
2009年 | 2篇 |
2008年 | 5篇 |
2007年 | 5篇 |
2006年 | 2篇 |
2005年 | 5篇 |
2004年 | 1篇 |
2003年 | 1篇 |
2002年 | 2篇 |
2001年 | 2篇 |
2000年 | 2篇 |
1999年 | 2篇 |
1998年 | 1篇 |
1995年 | 1篇 |
1994年 | 1篇 |
1993年 | 1篇 |
1992年 | 2篇 |
1991年 | 2篇 |
1990年 | 1篇 |
1989年 | 2篇 |
1988年 | 1篇 |
1987年 | 3篇 |
1986年 | 2篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1982年 | 2篇 |
1981年 | 3篇 |
1973年 | 1篇 |
1971年 | 2篇 |
1969年 | 1篇 |
1968年 | 2篇 |
1966年 | 3篇 |
排序方式: 共有108条查询结果,搜索用时 31 毫秒
71.
Shun Hirasawa Min Cho Tarsis F. Brust Jeremy J. Roach Laura M. Bohn Ryan A. Shenvi 《Bioorganic & medicinal chemistry letters》2018,28(16):2770-2772
Salvinorin A (SalA) is a potent and selective agonist of the kappa-opioid receptor (KOR), but its instability has frustrated medicinal chemistry efforts. Treatment of SalA with weak bases like DBU leads to C8 epimerization with loss of receptor affinity and signaling potency. Here we show that replacement of C20 with H and replacement of O6 with CH2 stabilizes the SalA scaffold relative to its C8 epimer, so much so that epimerization is completely supressed. This new compound, O6C-20-nor-SalA, retains high potency for agonism of KOR. 相似文献
72.
Christian Wiese Eva Große Maestrup Dirk Schepmann Stefan Grimme Hans‐Ulrich Humpf Peter Brust Bernhard Wünsch 《Chirality》2011,23(2):148-154
It was shown that racemic (±)‐ 2 [1′‐benzyl‐3‐(3‐fluoropropyl)‐3H‐spiro[[2]benzofuran‐1,4′‐piperidine], WMS‐1813 ] represents a promising positron emission tomography (PET) tracer for the investigation of centrally located σ1 receptors. To study the pharmacological activity of the enantiomers of 2 , a preparative HPLC separation of (R)‐2 and (S)‐2 was performed. The absolute configuration of the enantiomers was determined by CD‐spectroscopy together with theoretical calculations of the CD‐spectrum of a model compound. In receptor binding studies with the radioligand [3H]‐(+)‐pentazocine, (S)‐2 was thrice more potent than its (R)‐configured enantiomer (R)‐2 . The metabolic degradation of the more potent (S)‐enantiomer was considerably slower than the metabolism of (R)‐2 . The structures of the main metabolites of both enantiomers were elucidated by determination of the exact mass using an Orbitrap‐LC‐MS system. These experiments showed a stereoselective biotransformation of the enantiomers of 2 . Chirality, 2011. © 2010 Wiley‐Liss, Inc. 相似文献
73.
Gowri Chandra Sekhar KV Rao VS Deuther-Conrad W Reddy AS Brust P Krishna Kumar MM 《Journal of enzyme inhibition and medicinal chemistry》2011,26(4):561-568
A series of 2-{4-[4-(2,5-disubstituted thiazolyl)phenylethyl] piperazin-1-yl}-1,8-naphthyridine-3-carbonitriles were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were synthesized either by microwave irradiation technique or by conventional synthesis and were characterized by spectral data (IR, (1)H NMR, and MS) and the purity was ascertained by microanalysis. The D(2) and 5-HT(2A) affinity of the synthesized compounds was screened in vitro by radioligand displacement assays on membrane homogenates isolated from rat striatum and rat cortex, respectively. Furthermore, all the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. The D(2) antagonism studies were performed using climbing mouse assay model and 5-HT(2A) antagonism studies were performed using quipazine-induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy and 10f is the most active among the synthesized compounds with 5-HT(2A)/D(2) ratio of 1.1286 although the standard drug risperidone exhibited 5-HT(2A)/D(2) ratio of 1.0989. 相似文献
74.
Marcel Lindemann Sonja Hinz Winnie Deuther-Conrad Vigneshwaran Namasivayam Sladjana Dukic-Stefanovic Rodrigo Teodoro Magali Toussaint Mathias Kranz Cathleen Juhl Jörg Steinbach Peter Brust Christa E. Müller Barbara Wenzel 《Bioorganic & medicinal chemistry》2018,26(16):4650-4663
On the basis of a pyrazine core structure, three new adenosine A2B receptor ligands (7a–c) were synthesized containing a 2-fluoropyridine moiety suitable for 18F-labeling. Compound 7a was docked into a homology model of the A2B receptor based on X-ray structures of the related A2A receptor, and its interactions with the adenosine binding site were rationalized. Binding affinity data were determined at the four human adenosine receptor subtypes. Despite a rather low selectivity regarding the A1 receptor, 7a was radiolabeled as the most suitable candidate (Ki(A2B)?=?4.24?nM) in order to perform in vivo studies in mice with the aim to estimate fundamental pharmacokinetic characteristics of the compound class. Organ distribution studies and a single PET study demonstrated brain uptake of [18F]7a with a standardized uptake value (SUV) of ≈1 at 5?min post injection followed by a fast wash out. Metabolism studies of [18F]7a in mice revealed the formation of a blood–brain barrier penetrable radiometabolite, which could be structurally identified. The results of this study provide an important basis for the design of new derivatives with improved binding properties and metabolic stability in vivo. 相似文献
75.
New fluoro-diphenylchalcogen derivatives to explore the serotonin transporter by PET 总被引:1,自引:0,他引:1
Vercouillie J Deuther-Conrad W Scheunemann M Emond P Fischer S Funke U Steinbach J Guilloteau D Brust P 《Bioorganic & medicinal chemistry letters》2007,17(17):4991-4995
A series of fluorinated diphenylchalcogen derivatives, possessing a sulfur or an oxygen bridge, has been prepared with the aim to get a suitable radiotracer to image the SERT in vivo using positron emission tomography (PET). The compounds were synthesized and assayed toward the serotonin (SERT), dopamine (DAT), and norepinephrine (NET) transporters. Among the developed series, five compounds display a high SERT affinity (K(i): 0.27-2.91 nM range) and can be labeled either with carbon-11 or fluorine-18. 相似文献
76.
Drew LJ Rugiero F Cesare P Gale JE Abrahamsen B Bowden S Heinzmann S Robinson M Brust A Colless B Lewis RJ Wood JN 《PloS one》2007,2(6):e515
Little is known about the molecular basis of somatosensory mechanotransduction in mammals. We screened a library of peptide toxins for effects on mechanically activated currents in cultured dorsal root ganglion neurons. One conopeptide analogue, termed NMB-1 for noxious mechanosensation blocker 1, selectively inhibits (IC(50) 1 microM) sustained mechanically activated currents in a subset of sensory neurons. Biotinylated NMB-1 retains activity and binds selectively to peripherin-positive nociceptive sensory neurons. The selectivity of NMB-1 was confirmed by the fact that it has no inhibitory effects on voltage-gated sodium and calcium channels, or ligand-gated channels such as acid-sensing ion channels or TRPA1 channels. Conversely, the tarantula toxin, GsMTx-4, which inhibits stretch-activated ion channels, had no effects on mechanically activated currents in sensory neurons. In behavioral assays, NMB-1 inhibits responses only to high intensity, painful mechanical stimulation and has no effects on low intensity mechanical stimulation or thermosensation. Unexpectedly, NMB-1 was found to also be an inhibitor of rapid FM1-43 loading (a measure of mechanotransduction) in cochlear hair cells. These data demonstrate that pharmacologically distinct channels respond to distinct types of mechanical stimuli and suggest that mechanically activated sustained currents underlie noxious mechanosensation. NMB-1 thus provides a novel diagnostic tool for the molecular definition of channels involved in hearing and pressure-evoked pain. 相似文献
77.
Conotoxins exhibit a high degree of selectivity and potency for a range of pharmacologically relevant targets. The rapid access to libraries of conotoxin analogues, containing multiple intramolecular disulfide bridges for use in drug development, can be a very labor intensive, multi-step task. This work describes a high-throughput method for the synthesis of cystine-bridged conopeptides.Peptides were assembled on a peptide synthesizer employing the Fmoc solid-phase strategy using a safety-catch amide linker (SCAL). Side-chain protecting groups were removed on solid phase before SCAL activation with ammonium iodide in TFA, finally releasing the peptide into the TFA solution. Disulfide bond formation was performed in the cleavage mixture employing DMSO.This improved method allows mixtures of oxidized peptides to be obtained in parallel directly from a peptide synthesizer. A single HPLC purification of the resulting crude oxidized material produced peptides of > 95% purity. 相似文献
78.
Structural elements in domain IV that influence biophysical and pharmacological properties of human alpha1A-containing high-voltage-activated calcium channels
下载免费PDF全文
![点击此处可从《Biophysical journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Hans M Urrutia A Deal C Brust PF Stauderman K Ellis SB Harpold MM Johnson EC Williams ME 《Biophysical journal》1999,76(3):1384-1400
We have cloned two splice variants of the human homolog of the alpha1A subunit of voltage-gated Ca2+ channels. The sequences of human alpha1A-1 and alpha1A-2 code for proteins of 2510 and 2662 amino acids, respectively. Human alpha1A-2alpha2bdeltabeta1b Ca2+ channels expressed in HEK293 cells activate rapidly (tau+10mV = 2.2 ms), deactivate rapidly (tau-90mV = 148 micros), inactivate slowly (tau+10mV = 690 ms), and have peak currents at a potential of +10 mV with 15 mM Ba2+ as charge carrier. In HEK293 cells transient expression of Ca2+ channels containing alpha1A/B(f), an alpha1A subunit containing a 112 amino acid segment of alpha1B-1 sequence in the IVS3-IVSS1 region, resulted in Ba2+ currents that were 30-fold larger compared to wild-type (wt) alpha1A-2-containing Ca2+ channels, and had inactivation kinetics similar to those of alpha1B-1-containing Ca2+ channels. Cells transiently transfected with alpha1A/B(f)alpha2bdeltabeta1b expressed higher levels of the alpha1, alpha2bdelta, and beta1b subunit polypeptides as detected by immunoblot analysis. By mutation analysis we identified two locations in domain IV within the extracellular loops S3-S4 (N1655P1656) and S5-SS1 (E1740) that influence the biophysical properties of alpha1A. alpha1AE1740R resulted in a threefold increase in current magnitude, a -10 mV shift in steady-state inactivation, and an altered Ba2+ current inactivation, but did not affect ion selectivity. The deletion mutant alpha1ADeltaNP shifted steady-state inactivation by -20 mV and increased the fast component of current inactivation twofold. The potency and rate of block by omega-Aga IVA was increased with alpha1ADeltaNP. These results demonstrate that the IVS3-S4 and IVS5-SS1 linkers play an essential role in determining multiple biophysical and pharmacological properties of alpha1A-containing Ca2+ channels. 相似文献
79.
Evolutionary relatedness of some primate models of Plasmodium 总被引:1,自引:0,他引:1
Primate--and, specifically, monkey--malaria infections are commonly used
for understanding the pathology of and immune response to the human disease
because they are thought to resemble most closely the host-parasite
relationship found in humans. Plasmodium cynomolgi is used extensively as a
model for the human parasite, P. vivax, and P. knowlesi is used primarily
as a model for the development of erythrocytic-stage vaccines. Both of
these simian parasites can naturally infect man, resulting in mildly
symptomatic episodes of the disease. The phylogenetic relationship between
these two simian parasites and previously characterized Plasmodium species,
including P. vivax, was examined by comparison of the asexually expressed
small- subunit ribosomal RNA genes. Our analysis confirmed that P. vivax is
most closely related to P. cynomolgi and that it remains an appropriate
model of the human pathogen. Furthermore, with P. knowlesi and P. fragile,
these two species form a group of closely related species, distant from
other Plasmodium species. What is considered to be the most ancient of the
human malaria pathogens, P. malariae, was also included in the analysis and
does not group at all with other simian or human parasites.
相似文献
80.
Apoptosis pathways in fungal growth, development and ageing 总被引:2,自引:0,他引:2
Apoptosis is one type of programmed cell death with great importance for development and homeostasis of multicellular organisms. Unexpectedly, during the past decade, evidence has been obtained for the existence of a basal apoptosis machinery in yeast, as unicellular fungus, and in some filamentous fungi, a group of microorganisms that are neither true unicellular nor true multicellular biological systems but something in between. Here, we review evidence for a role of apoptotic processes in fungal pathogenicity, competitiveness, propagation, ageing and lifespan control. 相似文献