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11.
多肽在机体中具有重要的生理功能,并且它具有化学合成和修饰的便利性,因此它吸引了越来越多的化学、生物学及其交叉领域研究人员的研究兴趣。神经肽FF(NPFF)作为阿片调节肽在阿片耐受等药理学方面具有重要的调节作用,然而迄今为止仍缺乏NPFF受体高选择性的激动剂和拮抗剂,从而阻碍了NPFF药理学功能及其作用机制的研究。本文简述了NPFF的发现,并综述了近几年来在NPFF的前体、受体和生理学功能等方面所取得的最新进展,结合本实验室的工作重点介绍了NPFF构效关系方面的研究,并展望了该研究方向今后的发展趋势。 相似文献
12.
Wei Sun Linjie Tian Hui Qi Dan Jiang Ying Wang Song Li Junhai Xiao Xiaohong Yang 《中国化学》2013,(9):1144-1152
A series of tri-substituted chiral pyrrolidin-2-one derivatives have been designed and synthesized as CC chemokine receptor 4 (CCR4) antagonists. The structure of CCR4 was built by homology modeling. Asymmetric synthesis was applied to synthesize the R,R configuration chiral pyrrolidin-2-one scaffold. The stereoisomeric con- figurations of the compounds were identified by 2D I H-~H COSY spectroscopy and 1D NOESY spectroscopy. This method was more economical and convenient than traditional X-ray single crystal diffraction. In addition, the inter- actions between these compounds and the N-terminal extracellular tail of CCR4 were studied using capillary zone electrophoresis. The CCR4 chemotaxis inhibition effect was tested in CCR4-transfected HEK293 cells. Several compounds showed potent activities as CCR4 antagonists. Among these compounds, lc is the most active one. Its apparent binding constant of CZE experiment result is (1.569±0.11)× 10s L·mol ^-1, and its percentage inhibition of the HEK293/CCR4 cells migration with the concentration of I gmol·L ^-1 in DMSO is 59%. And compound If has slightly higher affinity to N-terminal of CCR4 according to its apparent binding constant than lb because of the in- troduced ester linkage. Further studies on the mechanism of these compounds are in progress. 相似文献
13.
Christos Liolios Christos Sachpekidis Antonios Kolocouris Antonia Dimitrakopoulou-Strauss Penelope Bouziotis 《Molecules (Basel, Switzerland)》2021,26(6)
Multimeric ligands consisting of multiple pharmacophores connected to a single backbone have been widely investigated for diagnostic and therapeutic applications. In this review, we summarize recent developments regarding multimeric radioligands targeting integrin αvβ3 receptors on cancer cells for molecular imaging and diagnostic applications using positron emission tomography (PET). Integrin αvβ3 receptors are glycoproteins expressed on the cell surface, which have a significant role in tumor angiogenesis. They act as receptors for several extracellular matrix proteins exposing the tripeptide sequence arginine-glycine-aspartic (RGD). Cyclic RDG peptidic ligands c(RGD) have been developed for integrin αvβ3 tumor-targeting positron emission tomography (PET) diagnosis. Several c(RGD) pharmacophores, connected with the linker and conjugated to a chelator or precursor for radiolabeling with different PET radionuclides (18F, 64Cu, and 68Ga), have resulted in multimeric ligands superior to c(RGD) monomers. The binding avidity, pharmacodynamic, and PET imaging properties of these multimeric c(RGD) radioligands, in relation to their structural characteristics are analyzed and discussed. Furthermore, specific examples from preclinical studies and clinical investigations are included. 相似文献
14.
Eleni Chontzopoulou Andreas G. Tzakos Thomas Mavromoustakos 《Molecules (Basel, Switzerland)》2021,26(1)
Antagonists of the AT1receptor (AT1R) are beneficial molecules that can prevent the peptide hormone angiotensin II from binding and activating the specific receptor causing hypertension in pathological states. This review article summarizes the multifaced applications of solid and liquid state high resolution nuclear magnetic resonance (NMR) spectroscopy in antihypertensive commercial drugs that act as AT1R antagonists. The 3D architecture of these compounds is explored through 2D NOESY spectroscopy and their interactions with micelles and lipid bilayers are described using solid state 13CP/MAS, 31P and 2H static solid state NMR spectroscopy. Due to their hydrophobic character, AT1R antagonists do not exert their optimum profile on the AT1R. Therefore, various vehicles are explored so as to effectively deliver these molecules to the site of action and to enhance their pharmaceutical efficacy. Cyclodextrins and polymers comprise successful examples of effective drug delivery vehicles, widely used for the delivery of hydrophobic drugs to the active site of the receptor. High resolution NMR spectroscopy provides valuable information on the physical-chemical forces that govern these drug:vehicle interactions, knowledge required to get a deeper understanding on the stability of the formed complexes and therefore the appropriateness and usefulness of the drug delivery system. In addition, it provides valuable information on the rational design towards the synthesis of more stable and efficient drug formulations. 相似文献
15.
Dr. Andreas Lerchen Dr. Narasimhulu Gandhamsetty Elliot H. E. Farrar Dr. Nils Winter Dr. Johannes Platzek Dr. Matthew N. Grayson Prof. Dr. Varinder K. Aggarwal 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(51):23307-23311
(−)-Finerenone is a nonsteroidal mineralocorticoid receptor antagonist currently in phase III clinical trials for the treatment of chronic kidney disease in type 2 diabetes. It contains an unusual dihydronaphthyridine core. We report a 6-step synthesis of (−)-finerenone, which features an enantioselective partial transfer hydrogenation of a naphthyridine using a chiral phosphoric acid catalyst with a Hantzsch ester. The process is complicated by the fact that the naphthyridine exists as a mixture of two atropisomers that react at different rates and with different selectivities. The intrinsic kinetic resolution was converted into a kinetic dynamic resolution at elevated temperature, which enabled us to obtain (−)-finerenone in both high yield and high enantioselectivity. DFT calculations have revealed the origin of selectivity. 相似文献
16.
Shaocheng Wang Siyong Lin Bo Xue Chenyu Wang Nana Yan Yueyan Guan Yuntao Hu Xuejun Wen 《Molecules (Basel, Switzerland)》2022,27(4)
Background: This study aimed to develop an ultrathin nanofibrous membrane able to, firstly, mimic the natural fibrous architecture of human Bruch’s membrane (BM) and, secondly, promote survival of retinal pigment epithelial (RPE) cells after surface functionalization of fibrous membranes. Methods: Integrin-binding peptides (IBPs) that specifically interact with appropriate adhesion receptors on RPEs were immobilized on Bruch’s-mimetic membranes to promote coverage of RPEs. Surface morphologies, Fourier-transform infrared spectroscopy spectra, contact angle analysis, Alamar Blue assay, live/dead assay, immunofluorescence staining, and scanning electron microscopy were used to evaluate the outcome. Results: Results showed that coated membranes maintained the original morphology of nanofibers. After coating with IBPs, the water contact angle of the membrane surfaces varied from 92.38 ± 0.67 degrees to 20.16 ± 0.81 degrees. RPE cells seeded on IBP-coated membranes showed the highest viability at all time points (Day 1, p < 0.05; Day 3, p < 0.01; Days 7 and 14, p < 0.001). The proliferation rate of RPE cells on uncoated poly(ε-caprolactone) (PCL) membranes was significantly lower than that of IBP-coated membranes (p < 0.001). SEM images showed a well-organized hexa/polygonal monolayer of RPE cells on IBP-coated membranes. RPE cells proliferated rapidly, contacted, and became confluent. RPE cells formed a tight adhesion with nanofibers under high-magnification SEM. Our findings confirmed that the IBP-coated PCL membrane improved the attachment, proliferation, and viability of RPE cells. In addition, in this study, we used serum-free culture for RPE cells and short IBPs without immunogenicity to prevent graft rejection and immunogenicity during transplantation. Conclusions: These results indicated that the biomimic BM-IBP-RPE nanofibrous graft might be a new, practicable approach to increase the success rate of RPE cell transplantation. 相似文献
17.
This paper presents the use of an HPLC method to assay nifedipine,nitrendipine,nimoldipine,nisoldip-ine,felodipine, m-nisoldipine concentration in human plasma simultaneously。 Separation was obtained using ODS column and mobile phase of acetonitrile-water(60:40,V/V)with flow rateof 1 mL/min。They were monitored with UV detector at 238 nm,The retention times for 6 drugs mentionedabove were 5.08,7.50,8.57,10.0,11. 91 and 12. 95 min,respectively。The recoveries were all 97%。 相似文献
18.
Sicen Wang Meng Sun Yanmin Zhang Hui DuLangchong He 《Journal of chromatography. A》2010,1217(32):5246-5252
The intracellular kinase domains of epidermal growth factor receptor (EGFR) in some tumor cells such as human epidermal squamous cells (A431 cells) are an important target for drug discovery. We have developed a new A431/cell membrane chromatography (A431/CMC)-online–high performance liquid chromatography/mass spectrometry (HPLC/MS) method for screening EGFR antagonists from medicinal herbs such as traditional Chinese medicines (TCMs). In this study, A431 cells with high EGFR expression levels were used to prepare cell membrane stationary phase (CMSP) in an A431/CMC model. The retention fractions eluted from the CMSP column were enriched onto an ODS pre-column and then switched into an HPLC/MS system by combining a 10 port columns switching valve. The screening results found that oxymatrine and matrine from Radix sophorae flavescentis (RSF) were the targeted components which could act on EGFR in similar manner of gefitinib as a control drug. There was a good relationship of their inhibiting effects on EGFR secretion and A431 cell growth in vitro. This new A431/CMC-online-HPLC/MS method can be applied for screening EGFR antagonists from TCMs such as RSF. It will be a useful method for drug discovery with natural medicinal herbs as a leading compound resource. 相似文献
19.
20.
Elisabetta Coppi Federica Cherchi Martina Venturini Elena Lucarini Renato Corradetti Lorenzo Di Cesare Mannelli Carla Ghelardini Felicita Pedata Anna Maria Pugliese 《Molecules (Basel, Switzerland)》2022,27(6)
Ligands of the Gi protein-coupled adenosine A3 receptor (A3R) are receiving increasing interest as attractive therapeutic tools for the treatment of a number of pathological conditions of the central and peripheral nervous systems (CNS and PNS, respectively). Their safe pharmacological profiles emerging from clinical trials on different pathologies (e.g., rheumatoid arthritis, psoriasis and fatty liver diseases) confer a realistic translational potential to these compounds, thus encouraging the investigation of highly selective agonists and antagonists of A3R. The present review summarizes information on the effect of latest-generation A3R ligands, not yet available in commerce, obtained by using different in vitro and in vivo models of various PNS- or CNS-related disorders. This review places particular focus on brain ischemia insults and colitis, where the prototypical A3R agonist, Cl-IB-MECA, and antagonist, MRS1523, have been used in research studies as reference compounds to explore the effects of latest-generation ligands on this receptor. The advantages and weaknesses of these compounds in terms of therapeutic potential are discussed. 相似文献