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1.
Cover Picture: Acetylcholine Promotes Binding of α‐Conotoxin MII at α3β2 Nicotinic Acetylcholine Receptors (ChemBioChem 3/2014) 下载免费PDF全文
Somisetti V. Sambasivarao Jessica Roberts Vivek S. Bharadwaj Jason G. Slingsby Conrad Rohleder Chris Mallory Prof. James R. Groome Prof. Owen M. McDougal Prof. C. Mark Maupin 《Chembiochem : a European journal of chemical biology》2014,15(3):337-337
2.
Edgar Luttmann Dr. Jürgen Ludwig Dr. Anja Höffle‐Maas Dr. Marek Samochocki Dr. Alfred Maelicke Prof. Dr. Gregor Fels Prof. Dr. 《ChemMedChem》2009,4(11):1874-1882
Current treatments of Alzheimer's disease include the allosteric potentiation of nicotinic acetylcholine receptor (nAChR) response. The location of the binding site for allosteric potentiating ligands (APLs) within the receptor is not yet fully understood. Based on homology models for the ligand binding domain of human α7, human α4β2, and chicken α7 receptors, as well as blind docking experiments with galanthamine, physostigmine, codeine, and 5HT, we identified T197 as an essential element of the APL binding site at the outer surface of the ligand binding domain (LBD) of nAChR. We also found the previously known galanthamine binding site in the region of K123 at the inside of the receptor funnel, which, however, was shown to not be part of the APL site. Our results are verified by site‐directed mutagenesis and electrophysiological experiments, and suggest that APL and ACh bind to different sites on nicotinic receptors and that allosteric potentiation may arise from a direct interplay between both these sites. 相似文献
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Synthesis and Pharmacological Evaluation of α4β2 Nicotinic Ligands with a 3‐Fluoropyrrolidine Nucleus 下载免费PDF全文
Dr. Lucia Tamborini Dr. Andrea Pinto Dr. Roberta Ettari Dr. Cecilia Gotti Dr. Francesca Fasoli Prof. Paola Conti Prof. Carlo De Micheli 《ChemMedChem》2015,10(6):1071-1078
Nicotinic acetylcholine receptors (nAChRs) play an important role in many central nervous system disorders such as Alzheimer’s and Parkinson’s diseases, schizophrenia, and mood disorders. The α4β2 subtype has emerged as an important target for the early diagnosis and amelioration of Alzheimer’s disease symptoms. Herein we report a new class of α4β2 receptor ligands characterized by a basic pyrrolidine nucleus, the basicity of which was properly decreased through the insertion of a fluorine atom at the 3‐position, and a pyridine ring carrying at the 3‐position substituents known to positively affect affinity and selectivity toward the α4β2 subtype. Derivatives 3‐(((2S,4R)‐4‐fluoropyrrolidin‐2‐yl)methoxy)‐5‐(phenylethynyl)pyridine ( 11 ) and 3‐((4‐fluorophenyl)ethynyl)‐5‐(((2S,4R)‐4‐fluoropyrrolidin‐2‐yl)methoxy)pyridine ( 12 ) were found to be the most promising ligands identified in this study, showing good affinity and selectivity for the α4β2 subtype and physicochemical properties predictive of a relevant central nervous system penetration. 相似文献
5.
Emma Langella Dr. Sébastien Pierre Dr. Wadih Ghattas Dr. Michel Giorgi Dr. Marius Réglier Dr. Michele Saviano Dr. Luciana Esposito Dr. Renaud Hardré Dr. 《ChemMedChem》2010,5(9):1568-1576
Specific inhibition of the copper‐containing peptidylglycine α‐hydroxylating monooxygenase (PHM), which catalyzes the post‐translational modification of peptides involved in carcinogenesis and tumor progression, constitutes a new approach for combating cancer. We carried out a structure–activity study of new compounds derived from a well‐known PHM substrate analogue, the olefinic compound 4‐phenyl‐3‐butenoic acid (PBA). We designed, synthesized, and tested various PBA derivatives both in vitro and in silico. We show that it is possible to increase PBA affinity for PHM by appropriate functionalization of its aromatic nucleus. Compound 2 d , for example, bears a meta‐benzyloxy substituent, and exhibits better inhibition features (Ki=3.9 μM , kinact/Ki=427 M ?1 s?1) than the parent PBA (Ki=19 μM , kinact/Ki=82 M ?1 s?1). Docking calculations also suggest two different binding modes for PBA derivatives; these results will aid in the development of further PHM inhibitors with improved features. 相似文献
6.
Tommaso Angelini Daniela Lanari Raimondo Maggi Ferdinando Pizzo Giovanni Sartori Luigi Vaccaro 《Advanced Synthesis \u0026amp; Catalysis》2012,354(5):908-916
Novel solid fluorides were prepared to optimize the β‐azidation of α,β‐unsaturated ketones. The higher loading of these catalysts compared to that of commercially available fluorides has allowed the use of a smaller mass of catalyst helping the mixing of the reaction mixture. Porous polymeric supports have proved to be more efficient in the presence of water as reaction medium. Water has played a crucial role showing a beneficial effect on the reactivity by improving dispersion of the reaction mixture and also by avoiding organic fouling caused by the retention of the reaction mixture within the polymeric matrix. This has facilitated the recovery of the products from the catalyst. The protocol reported has allowed a significant reduction in the organic solvent required for the complete recovery of the pure product whilst leaving the catalyst clean and reusable. E‐factors are in the range of 5.9–10.5 and therefore ca. 3 times smaller than previous procedures operating under solvent‐free conditions. To further improve the efficiency of our approach we have developed a protocol operating in a continuous‐flow manner that has allowed us to achieve an E‐factor of 1.7–1.9, with a reduction of ca. 80% of the corresponding batch conditions. The continuous‐flow protocol has allowed us to minimize the use of trimethylsilyl azide making the recovery and reuse of water and catalyst 5f very efficient and simple. Finally, a novel reduction system using palladium on alumina (5 mol%) and equimolar amount of formic acid has been used in the presence of 1 equivalent of di‐tert‐butyl pyrocarbonate to set a multistep protocol operating in continuous‐flow conditions for the preparation of two representative N‐Boc‐β‐amino ketones starting from the corresponding enones with E‐factors of 3.2 and 2.7, respectively. 相似文献
7.
Francis A. Acquah Matthew Paramel Adama Kuta Syed R. Hussaini David R. Wallace Blaine H. M. Mooers 《International journal of molecular sciences》2021,22(15)
Smoking-cessation drugs bind many off-target nicotinic acetylcholine receptors (nAChRs) and cause severe side effects if they are based on nicotine. New drugs that bind only those receptors, such as 62* nAChR, implicated in nicotine addiction would avoid the off-target binding. Indolizidine (-)-237D (IND (-)-237D), a bicyclic alkaloid, has been shown to block 62* containing nAChRs and functionally inhibit the nicotine-evoked dopamine release. To improve the affinity of indolizidine (-)-237D for 62*, we built a library of 2226 analogs. We screened virtually the library against a homology model of 62 nAChR that we derived from the recent crystal structure of 42 nAChR. We also screened the crystal structure of 42 nAChR as a control on specificity. We ranked the compounds based on their predicted free energy of binding. We selected the top eight compounds bound in their best pose and subjected the complexes to 100 ns molecular dynamics simulations to assess the stability of the complexes. All eight analogs formed stable complexes for the duration of the simulations. The results from this work highlight nine distinct analogs of IND (-)-237D with high affinity towards 62* nAChR. These leads can be synthesized and tested in in vitro and in vivo studies as lead candidates for drugs to treat nicotine addiction. 相似文献
8.
Nathalia M. Pinheiro Rosana Banzato Iolanda Tibrio Marco A. M. Prado Vnia F. Prado Ayman K. Hamouda Carla M. Prado 《International journal of molecular sciences》2021,22(14)
(1) Background: The lung cholinergic pathway is important for controlling pulmonary inflammation in acute lung injury, a condition that is characterized by a sudden onset and intense inflammation. This study investigated changes in the expression levels of nicotinic and muscarinic acetylcholine receptors (nAChR and mAChR) in the lung during acute lung injury. (2) Methods: acute lung injury (ALI) was induced in wild-type and cholinergic-deficient (VAChT-KDHOM) mice using intratracheal lipopolysaccharide (LPS) instillation with or without concurrent treatment with nicotinic ligands. Bronchoalveolar lavage fluid was collected to evaluate markers of inflammation, and then the lung was removed and processed for isolation of membrane fraction and determination of acetylcholine receptors level using radioligand binding assays. (3) Results: LPS-induced increase in lung inflammatory markers (e.g., neutrophils and IL-1β) was significantly higher in VAChT-KDHOM than wild-type mice. In contrast, LPS treatment resulted in a significant increase in lung’s α7 nicotinic receptor level in wild-type, but not in VAChT-KDHOM mice. However, treatment with PNU 282987, a selective α7 nicotinic receptor agonist, restored VAChT-KDHOM mice’s ability to increase α7 nicotinic receptor levels in response to LPS-induced acute lung injury and reduced lung inflammation. LPS also increased muscarinic receptors level in VAChT-KDHOM mice, and PNU 282987 treatment reduced this response. (4) Conclusions: Our data indicate that the anti-inflammatory effects of the lung cholinergic system involve an increase in the level of α7 nicotinic receptors. Pharmacological agents that increase the expression or the function of lung α7 nicotinic receptors have potential clinical uses for treating acute lung injury. 相似文献
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Claudia Sorbi Dr. Silvia Franchini Dr. Annalisa Tait Prof. Adolfo Prandi Dr. Rossella Gallesi Piero Angeli Prof. Gabriella Marucci Prof. Lorenza Pirona Dr. Elena Poggesi Dr. Livio Brasili Prof. 《ChemMedChem》2009,4(3):393-399
Conformational restriction of naftopidil led to the discovery of a new class of ligands with a 1,3‐dioxolane (1,3‐oxathiolane, 1,3‐dithiolane) structure that bind to α1 adrenoceptor subtypes and 5‐HT1A receptors. Adequate structural modifications address the selectivity toward one or the other receptor system.
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Laxmidhar Rout Sridhar Regati Cong‐Gui Zhao 《Advanced Synthesis \u0026amp; Catalysis》2011,353(18):3340-3346
Efficient methods for the direct arylation and deacylative arylation of β‐ketophosphonates with iodoarenes in presence of a copper(I) or a copper(II) salt as the catalysts have been developed. The corresponding α‐arylphosphonates were obtained in high yields. A tentative mechanism for the deacylative arylation reaction was proposed on the basis of the experimental data. 相似文献
11.
α‐Substituted β‐acetyl amides could undergo C C bond cleavage to form α‐keto amides when treated with copper(II) chloride (CuCl2) and boron trifluoride diethyl etherate (BF3⋅OEt2) under an oxygen atmosphere. The yield can be increased by the addition of tert‐butyl hydroperoxide which alone can also effect the reaction. The reaction provides a new protocol for the synthesis of α‐keto amides.
12.
Gaetano Giammona Gennara Cavallaro Giovanna Pitarresi Elisa Pedone 《Polymer International》2000,49(1):93-98
In the present study the derivatization of two water‐soluble synthetic polymers, α,β‐poly(N‐2‐hydroxyethyl)‐DL ‐aspartamide (PHEA) and α,β‐polyasparthylhydrazide (PAHy), with glycidyltrimethylammonium chloride (GTA) is described. This reaction permits the introduction of positive charges in the macromolecular chains of PHEA and PAHy in order to make easier the electrostatic interaction with DNA. Different parameters affect the reaction of derivatization, such as GTA concentration and reaction time. PHEA reacts partially and slowly with GTA; on the contrary the reaction of PAHy with GTA is more rapid and extensive. The derivatization of PHEA and PAHy with GTA is a convenient method to introduce positive groups in their chains and it permits the preparation of interpolyelectrolyte complexes with DNA. © 2000 Society of Chemical Industry 相似文献
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Makoto Hibi Takuya Kasahara Takashi Kawashima Hiroko Yajima Shoko Kozono Sergey V. Smirnov Tomohiro Kodera Masakazu Sugiyama Sakayu Shimizu Kenzo Yokozeki Jun Ogawa 《Advanced Synthesis \u0026amp; Catalysis》2015,357(4):767-774
A novel enzymatic production system of optically pure β‐hydroxy α‐amino acids was developed. Two enzymes were used for the system: an N‐succinyl L ‐amino acid β‐hydroxylase (SadA) belonging to the iron(II)/α‐ketoglutarate‐dependent dioxygenase superfamily and an N‐succinyl L ‐amino acid desuccinylase (LasA). The genes encoding the two enzymes are part of a gene set responsible for the biosynthesis of peptidyl compounds found in the Burkholderia ambifaria AMMD genome. SadA stereoselectively hydroxylated several N‐succinyl aliphatic L ‐amino acids and produced N‐succinyl β‐hydroxy L ‐amino acids, such as N‐succinyl‐L ‐β‐hydroxyvaline, N‐succinyl‐L ‐threonine, (2S,3R)‐N‐succinyl‐L ‐β‐hydroxyisoleucine, and N‐succinyl‐L ‐threo‐β‐hydroxyleucine. LasA catalyzed the desuccinylation of various N‐succinyl‐L ‐amino acids. Surprisingly, LasA is the first amide bond‐forming enzyme belonging to the amidohydrolase superfamily, and has succinylation activity towards the amino group of L ‐leucine. By combining SadA and LasA in a preparative scale production using N‐succinyl‐L ‐leucine as substrate, 2.3 mmol of L ‐threo‐β‐hydroxyleucine were successfully produced with 93% conversion and over 99% of diastereomeric excess. Consequently, the new production system described in this study has advantages in optical purity and reaction efficiency for application in the mass production of several β‐hydroxy α‐amino acids.
14.
Krishna Bahadur SomaiMagar Yong Rok Lee 《Advanced Synthesis \u0026amp; Catalysis》2014,356(16):3422-3432
Efficient one‐step syntheses of α,β‐ and β,β‐dihaloenones were achieved by ruthenium(II)‐catalyzed reactions between cyclic or acyclic diazodicarbonyl compounds and oxalyl chloride or oxalyl bromide in moderate to good yields. This methodology offers several significant advantages, which include ease of handling, mild reaction conditions, one‐step reaction, and the use of an effective and non‐toxic catalyst. The synthesized compounds were further transformed into highly functionalized novel molecules bearing aromatic rings on the enone moiety using the Suzuki reaction.
15.
Poly‐α,β‐(3‐hydroxypropyl)‐DL ‐aspartamide (PHPA) was synthesized by the ring‐open reaction of polysuccinimide (PSI) and 3‐hydroxypropylamine. The polymer was characterized by 1H‐NMR, 13C‐NMR, FTIR, and GPC. Mark–Houwink coefficients were obtained from viscometry and GPC measurements, K = 5.53 × 10−3 and α = 0.78 in water. The acute toxicity of PHPA was examined and it revealed no death in ICR mice up to the dose treated of 15.3 kg/kg, and hematological parameters showed no significant difference between treated and control animals. The potential use of PHPA as a drug carrier was also investigated. In a typical case, a contraceptive drug, norethindrone (NET), was bonded to PHPA, and the drug sustained released as long as 120 days an in vitro test. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 77: 2411–2417, 2000 相似文献
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Min Woo Ha Heejin Lee Hye Yeong Yi Yohan Park Sori Kim Suckchang Hong Myungmo Lee Mi‐hyun Kim Taek‐Soo Kim Hyeung‐geun Park 《Advanced Synthesis \u0026amp; Catalysis》2013,355(4):637-642
A new enantioselective α‐benzylation and α‐allylation of α‐tert‐butoxycarbonyllactones was devloped. α‐Benzylation and α‐allylation of α‐tert‐butoxycarbonylbutyrolactone and α‐tert‐butoxycarbonylvalerolactone under phase‐transfer catalytic conditions (50% cesium hydroxide, toluene, −60 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐NAS bromide (1 mol%) afforded the corresponding α‐substituted α‐tert‐butoxycarbonyllactones in very high chemical yields (up to 99%) and optical yields (up to 99% ee). The synthetic potential of this method has been successfully demonstrated by the asymmetric synthesis of unnatural α‐quaternary homoserines, 3‐alkyl‐3‐carboxypyrrolidine and 3‐alkyl‐3‐carboxypiperidine. 相似文献
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Dr. Danielle L. Aubele Dr. Roy K. Hom Dr. Marc Adler Dr. Robert A. Galemmo Jr. Dr. Simeon Bowers Dr. Anh P. Truong Dr. Hu Pan Dr. Paul Beroza Dr. R. Jeffrey Neitz Dr. Nanhua Yao May Lin Dr. George Tonn Heather Zhang Dr. Michael P. Bova Dr. Zhao Ren Danny Tam Lany Ruslim Dr. Jeanne Baker Linnea Diep Dr. Kent Fitzgerald Jennifer Hoffman Ruth Motter Donald Fauss Pearl Tanaka Dr. Michael Dappen Dr. Jacek Jagodzinski Wayman Chan Dr. Andrei W. Konradi Dr. Lee Latimer Dr. Yong L. Zhu Dr. Hing L. Sham Dr. John P. Anderson Dr. Marcelle Bergeron Dr. Dean R. Artis 《ChemMedChem》2013,8(8):1295-1313
Polo‐like kinase‐2 (Plk‐2) has been implicated as the dominant kinase involved in the phosphorylation of α‐synuclein in Lewy bodies, which are one of the hallmarks of Parkinson’s disease neuropathology. Potent, selective, brain‐penetrant inhibitors of Plk‐2 were obtained from a structure‐guided drug discovery approach driven by the first reported Plk‐2–inhibitor complexes. The best of these compounds showed excellent isoform and kinome‐wide selectivity, with physicochemical properties sufficient to interrogate the role of Plk‐2 inhibition in vivo. One such compound significantly decreased phosphorylation of α‐synuclein in rat brain upon oral administration and represents a useful probe for future studies of this therapeutic avenue toward the potential treatment of Parkinson’s disease. 相似文献
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Yohan Park Young Ju Lee Suckchang Hong Mi‐hyun Kim Myungmo Lee Taek‐Soo Kim Jae Kyun Lee Sang‐sup Jew Hyeung‐geun Park 《Advanced Synthesis \u0026amp; Catalysis》2011,353(18):3313-3318
A new enantioselective α‐alkylation of α‐tert‐butoxycarbonyllactams for the construction of β‐quaternary chiral pyrrolidine and piperidine core systems is reported. α‐Alkylations of N‐methyl‐α‐tert‐butoxycarbonylbutyrolactam and N‐diphenylmethyl‐α‐tert‐butoxycarbonylvalerolactam under phase‐transfer catalytic conditions (solid potassium hydroxide, toluene, −40 °C) in the presence of (S,S)‐3,4,5‐trifluorophenyl‐3,3′,5,5′‐tetrahydro‐2,6‐bis(3,4,5‐trifluorophenyl)‐4,4′‐spirobi[4H‐dinaphth[2,1‐c:1′,2′‐e]azepinium] bromide [(S,S)‐NAS Br] (5 mol%) afforded the corresponding α‐alkyl‐α‐tert‐butoxycarbonyllactams in very high chemical (up to 99%) and optical yields (up to 98% ee). Our new catalytic systems provide attractive synthetic methods for pyrrolidine‐ and piperidine‐based alkaloids and chiral intermediates with β‐quaternary carbon centers. 相似文献
19.
Jian‐Xin Ji TerryT.‐L. Au‐Yeung Jing Wu ChiuWing Yip AlbertS.C. Chan 《Advanced Synthesis \u0026amp; Catalysis》2004,346(1):42-44
The first catalytic synthesis of β,γ‐alkynyl α‐amino acid derivatives was achieved by direct addition of terminal alkynes to α‐imino esters in the presence of an Ag(I) salt under mild reaction conditions. 相似文献