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1.
David C. Kombo Vladimir P. Grinevich Terry A. Hauser Serguei Sidach Merouane Bencherif 《Bioorganic & medicinal chemistry letters》2013,23(17):4842-4847
Compounds containing a quinuclidine scaffold are promising drug candidates for pharmacological management of the central nervous system (CNS) pathologies implicating nAChRs. We have carried out binding affinity and in-silico docking studies of arylmethylene quinuclidine-like derivatives at the α4β2 receptor using in-vitro receptor binding assay and comparative modeling, respectively. We found that introducing a hydrogen-bond acceptor into the 3-benzylidene quinuclidine derivative resulted in a 266-fold increase in binding affinity and confers agonism properties. By contrast, addition of a phenyl group to 3-benzylidene quinuclidine derivative only results in an 18-fold increase in binding affinity, without conferring agonism. We also found that docking into the orthosteric binding site of the α4β2 nAChR is consistent with the fact that the basic nitrogen atom donates a hydrogen-bond to the carbonyl group of the highly conserved Trp-149, as initially observed by Dougherty and co-workers.1 The experimentally-observed trend in binding affinity at both α4β2 and α3β4 nAChRs was accurately and independently confirmed by quantum mechanics (QM)-polarized docking. The reduction in binding affinity to the α3β4 subtype primarily results from a dampening of both coulombic and cation–π interactions. 相似文献
2.
Fang Zheng Guangrong Zheng A. Gabriela Deaciuc Chang-Guo Zhan Linda P. Dwoskin 《Journal of enzyme inhibition and medicinal chemistry》2013,28(1):157-168
Based on an 85 molecule database, linear regression with different size datasets and an artificial neural network approach have been used to build mathematical relationships to fit experimentally obtained affinity values (Ki) of a series of mono- and bis-quaternary ammonium salts from [3H]nicotine binding assays using rat striatal membrane preparations. The fitted results were then used to analyze the pattern among the experimental Ki values of a set of N-n-alkylnicotinium analogs with increasing n-alkyl chain length from 1 to 20 carbons. The affinity of these N-n-alkylnicotinium compounds was shown to parabolically vary with increasing numbers of carbon atoms in the n-alkyl chain, with a local minimum for the C4 (n-butyl) analogue. A decrease in Ki value between C12 and C13 was also observed. The statistical results for the best neural network fit of the 85 experimental Ki values are r2 = 0.84, rmsd = 0.39; rcv2 = 0.68, and loormsd = 0.56. The generated neural network model with the 85 molecule training set may also be of value for future predictions of Ki values for new virtual compounds, which can then be identified, subsequently synthesized, and tested experimentally. 相似文献
3.
Dallanoce C Matera C Pucci L Gotti C Clementi F Amici MD Micheli CD 《Bioorganic & medicinal chemistry letters》2012,22(2):829-832
A group of novel racemic nicotinic ligands structurally related to epibatidine or epiboxidine [(±)-10-(±)-17] was synthesized through a palladium-catalyzed cross-coupling between the appropriate vinyl triflate and a range of organometallic heterocycles. The target compounds were evaluated for binding affinity at the α4β2 and α7 neuronal nicotinic receptors (nAChRs). The set of 3-pyridinyl derivatives (±)-10, (±)-11 and (±)-12 exhibited an affinity for the α4β2 nAChR subtype in the subnanomolar range (K(i) values of 0.20, 0.40 and 0.50nM, respectively) and behaved as α4β2 versus α7 subtype selective ligands. Interestingly, the epiboxidine-related dimethylammonium iodide (±)-17, which retained a good affinity for the α4β2 nAChR (K(i)=13.30nM), tightly bound also to the α7 subtype (K(i)=1.60nM), thus displaying a reversal of the affinity trend among the reference and new nicotinic ligands under investigation. 相似文献
4.
Dallanoce C Matera C De Amici M Rizzi L Pucci L Gotti C Clementi F De Micheli C 《Chirality》2012,24(7):543-551
Epiboxidine hydrochlorides (+)-2 and (-)-2, which are the structural analogs of the antipodes of epibatidine (±)-1, as well as the enantiomeric pairs (+)-3/(-)-3 and (+)-4/(-)-4 were synthesized and tested for binding affinity at α4β2 and α7 nicotinic acetylcholine receptor (nAChR) subtypes. Final derivatives were prepared through the condensation of racemic N-Boc-7-azabicyclo[2.2.1]heptane-2-one (±)-5 with the resolving agent (R)-(+)-2-methyl-2-propanesulfinamide. The pharmacological analysis carried out on the three new enantiomeric pairs evidenced an overall negligible degree of enantioselectivity at both nAChRs subtypes, a result similar to that reported for both natural and unnatural epibatidine enantiomers at the same investigated receptor subtypes. 相似文献
5.
In recent years, it has become clear that the neuronal nicotinic acetylcholine receptor (nAChR) is a valid target in the treatment
of a variety of diseases, including Alzheimer’s disease, anxiety, and nicotine addiction. As with most membrane proteins,
information on the three-dimensional (3D) structure of nAChR is limited to data from electron microscopy, at a resolution
that makes the application of structure-based design approaches to develop specific ligands difficult. Based on a high-resolution
crystal structure of AChBP, homology models of the extracellular domain of the neuronal rat and human nAChR subtypes α4β2
and α7 (the subtypes most abundant in brain) were built, and their stability assessed with molecular dynamics (MD). All models
built showed conformational stability over time, confirming the quality of the starting 3D model. Lipophilicity and electrostatic
potential studies performed on the rat and human α4β2 and α7 nicotinic models were compared to AChBP, revealing the importance
of the hydrophobic aromatic pocket and the critical role of the α-subunit Trp—the homolog of AChBP-Trp 143—for ligand binding.
The models presented provide a valuable framework for the structure-based design of specific α4β2 nAChR subtype ligands aimed
at improving therapeutic and diagnostic applications.
Figure Electrostatic surface potential of the binding site cavity of the neuronal nicotinic acetylcholine receptor (nAChR). Nicotinic
models performed with the MOLCAD program: a rat α7, b rat α4β2, c human α7, d human α4β2. All residues labeled are part of the α7 (a,c) or α4 (b,d) subunit with the exception of Phe 117, which belongs to subunit β2 (d). Violet Very negative, blue negative, yellow neutral, red very positive 相似文献
6.
George AA Lucero LM Damaj MI Lukas RJ Chen X Whiteaker P 《The Journal of biological chemistry》2012,287(30):25151-25162
Genome-wide studies have strongly associated a non-synonymous polymorphism (rs16969968) that changes the 398th amino acid in the nAChR α5 subunit from aspartic acid to asparagine (D398N), with greater risk for increased nicotine consumption. We have used a pentameric concatemer approach to express defined and consistent populations of α3β4α5 nAChR in Xenopus oocytes. α5(Asn-398; risk) variant incorporation reduces ACh-evoked function compared with inclusion of the common α5(Asp-398) variant without altering agonist or antagonist potencies. Unlinked α3, β4, and α5 subunits assemble to form a uniform nAChR population with pharmacological properties matching those of concatemeric α3β4* nAChRs. α5 subunit incorporation reduces α3β4* nAChR function after coinjection with unlinked α3 and β4 subunits but increases that of α3β4α5 versus α3β4-only concatemers. α5 subunit incorporation into α3β4* nAChR also alters the relative efficacies of competitive agonists and changes the potency of the non-competitive antagonist mecamylamine. Additional observations indicated that in the absence of α5 subunits, free α3 and β4 subunits form at least two further subtypes. The pharmacological profiles of these free subunit α3β4-only subtypes are dissimilar both to each other and to those of α3β4α5 nAChR. The α5 variant-induced change in α3β4α5 nAChR function may underlie some of the phenotypic changes associated with this polymorphism. 相似文献
7.
Synthesis and initial evaluation of novel,non-peptidic antagonists of the αv-integrins αvβ3 and αvβ5
Jeffrey J. Letourneau Jinqi Liu Michael H.J. Ohlmeyer Chris Riviello Yajing Rong Hong Li Kenneth C. Appell Shalini Bansal Biji Jacob Angela Wong Maria L. Webb 《Bioorganic & medicinal chemistry letters》2009,19(2):352-355
The discovery, synthesis and preliminary SAR of a novel class of non-peptidic antagonists of the αv-integrins αvβ3 and αvβ5 is described. High-throughput screening of an extensive series of ECLiPS? compound libraries led to the identification of compound 1 as a dual inhibitor of the αv-integrins αvβ3 and αvβ5. Optimization of compound 1 involving, in part, introduction of two novel constraints led to the discovery of compounds 15a and 15b with reduced PSA and much improved potency for both the αvβ3 and αvβ5 integrins. Compounds 15a and 15b were shown to have promising activity in functional cellular assays and compound 15a also exhibited a promising Caco-2 permeability profile. 相似文献
8.
Acetylcholine-based neurotransmission is regulated by cationic, ligand-gated ion channels called nicotinic acetylcholine receptors (nAChRs). These receptors have been linked to numerous neurological diseases and disorders such as Alzheimer's disease, Parkinson's disease, and nicotine addiction. Recently, a class of compounds has been discovered that antagonize nAChR function in an allosteric fashion. Models of human α4β2 and α3β4 nicotinic acetylcholine receptor (nAChR) extracellular domains have been developed to computationally explore the binding of these compounds, including the dynamics and free energy changes associated with ligand binding. Through a blind docking study to multiple receptor conformations, the models were used to determine a putative binding mode for the negative allosteric modulators. This mode, in close proximity to the agonist binding site, is presented in addition to a hypothetical mode of antagonism that involves obstruction of C loop closure. Molecular dynamics simulations and MM-PBSA free energy of binding calculations were used as computational validation of the predicted binding mode, while functional assays on wild-type and mutated receptors provided experimental support. Based on the proposed binding mode, two residues on the β2 subunit were independently mutated to the corresponding residues found on the β4 subunit. The T58K mutation resulted in an eight-fold decrease in the potency of KAB-18, a compound that exhibits preferential antagonism for human α4β2 over α3β4 nAChRs, while the F118L mutation resulted in a loss of inhibitory activity for KAB-18 at concentrations up to 100 μM. These results demonstrate the selectivity of KAB-18 for human α4β2 nAChRs and validate the methods used for identifying the nAChR modulator binding site. Exploitation of this site may lead to the development of more potent and subtype-selective nAChR antagonists which may be used in the treatment of a number of neurological diseases and disorders. 相似文献
9.
Ayman K. Hamouda Mitesh Sanghvi Akash Pandhare Joe Henry Steinbach 《生物化学与生物物理学报:生物膜》2009,1788(9):1987-807
The development of nicotinic acetylcholine receptor (nAChR) agonists, particularly those that discriminate between neuronal nAChR subtypes, holds promise as potential therapeutic agents for many neurological diseases and disorders. To this end, we photoaffinity labeled human α4β2 and rat α4β4 nAChRs affinity-purified from stably transfected HEK-293 cells, with the agonists [125I]epibatidine and 5[125I]A-85380. Our results show that both agonists photoincorporated into the β4 subunit with little or no labeling of the β2 and α4 subunits respectively. [125I]epibatidine labeling in the β4 subunit was mapped to two overlapping proteolytic fragments that begin at β4V102 and contain Loop E (β4I109-P120) of the agonist binding site. We were unable to identify labeled amino acid(s) in Loop E by protein sequencing, but we were able to demonstrate that β4Q117 in Loop E is the principal site of [125I]epibatidine labeling. This was accomplished by substituting residues in the β2 subunit with the β4 homologs and finding [125I]epibatidine labeling in β4 and β2F119Q subunits with little, if any, labeling in α4, β2, or β2S113R subunits. Finally, functional studies established that the β2F119/β4Q117 position is an important determinant of the receptor subtype-selectivity of the agonist 5I-A-85380, affecting both binding affinity and channel activation. 相似文献
10.
HMBPP ((E)-4-hydroxy-3-methyl-2-butenyl pyrophosphate) is a highly potent innate immunogen that stimulates human γδ T cells expressing the Vγ2Vδ2 T cell antigen receptor. To determine if glycoside conjugates of HMBPP retain activity, the 4-β-glucoside and its acetylated homolog were synthesized and tested for their ability to stimulate γδ T cells. The glycoside HMBPP conjugate stimulated human γδ T cells with an EC(50) of 78nM. The tetraacetyl glycoside HMBPP conjugate was also active (EC(50)=360nM). The two isomeric mono-β-glucosides of the parent (E)-2-methylbut-2-ene-1,4-diol, however, were not active. Thus, HMBPP glycosylated at the 4-OH position stimulates γδ T cells as long as the pyrophosphate moiety is present. 相似文献
11.
Hiroshi Ohrui Tsutami Misawa Hiroshi Meguro 《Bioscience, biotechnology, and biochemistry》2013,77(7):1825-1829
The photobromination of 1,5-anhydro-2,3-O-isopropylidene-β-d-ribofuranose gave the corresponding (5S)-5-bromo compound. The reduction of the bromide with triphenyltindeuteride gave (5S)-(5-2H1)-1,5-anhydro-2,3-O-isopropylidene-β-d-ribofuranose, with a chiral purity of 76% at C-5, which was converted to (5R)- and (5S)-(5-2H1)-d-riboses and other ribofuranose derivatives. 相似文献
12.
D. Morris 《The Biochemical journal》1960,76(2):349-353
13.
《Bioorganic & medicinal chemistry》2016,24(2):247-260
The covalent modification of peroxisome-proliferator activated receptor β/δ (PPARβ/δ) is part of the mode of action of 5-trifluoromethyl-2-sulfonylpyridine PPARβ/δ antagonists such as GSK3787 and CC618. Herein, the synthesis and in vitro biological evaluation of a range of structural analogues of the two antagonists are reported. The new ligands demonstrate that an improvement in the selectivity of 5-trifluoromethyl-2-sulfonylpyridine antagonists towards PPARβ/δ is achievable at the expense of their immediate affinity for PPARβ/δ. However, their putatively covalent and irreversible mode of action may ensure their efficacy over time, as observed in time-resolved fluorescence resonance energy transfer (TR-FRET)-based ligand displacement assays. 相似文献
14.
JIANHONG CHEN AGRIPINA G. DEACIUC LINDA P. DWOSKIN PETER A. CROOKS DONGLU BAI 《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):667-680
A series of N, N– disubstituted piperazines and homopiperazines were prepared and evaluated for binding to natural α4β2* and α7* neuronal nicotinic acetylcholine receptors (nAChRs) using whole brain membrane. Some compounds exhibited good selectivity for α4β2* nAChRs and did not interact with the α7* nAChRs subtype. The most potent analogs were compounds 8-19 (Ki = 10.4 μM), 8–13 (Ki = 12.0 μM), and 8–24 (Ki = 12.8 μM). Thus, linking together a pyridine π-system and a cyclic amine moiety via a homopiperazine ring affords compounds with low affinity but with good selectivity for α4β2* nAChRs. 相似文献
15.
16.
Yongjun Gao Hayden T. Ravert Hiroto Kuwabara Yingxian Xiao Christopher J. Endres John Hilton Daniel P. Holt Anil Kumar Mohab Alexander Dean F. Wong Robert F. Dannals Andrew G. Horti 《Bioorganic & medicinal chemistry》2009,17(13):4367-4377
The most abundant subtype of cerebral nicotinic acetylcholine receptors (nAChR), α4β2, plays a critical role in various brain functions and pathological states. Imaging agents suitable for visualization and quantification of α4β2 nAChRs by positron emission tomography (PET) would present unique opportunities to define the function and pharmacology of the nAChRs in the living human brain. In this study, we report the synthesis, nAChR binding affinity, and pharmacological properties of several novel 3-pyridyl ether compounds. Most of these derivatives displayed a high affinity to the nAChR and a high subtype selectivity for α4β2-nAChR. Three of these novel nAChR ligands were radiolabeled with the positron-emitting isotope 11C and evaluated in animal studies as potential PET radiotracers for imaging of cerebral nAChRs with improved brain kinetics. 相似文献
17.
Pieter E. Joos Eddy L. Esmans Roger A. Dommisse Walter Van Dongen Jozef A. Lepoivre Frank C. Alderweireldt 《Nucleosides, nucleotides & nucleic acids》2013,32(4):883-894
Abstract D-Allo/D-altro 2-(2,4:3, 5-di-O-benzylidenepentitol-1-y1)-4-(4,4-dimethyloxazolin-2-y1)pyridine was synthesized from 2-lithio-4-(4,4-dimethyloxazolin-2-y1)pyridine and 2, 4:3,5-di-O-benzylidenealdehydo-D-ribose. After mesylation and subsequent treatment of the adduct with CF3COOH/H2O and then ammonia, 4-carbamoyl-2-D-ribofuranosylpyridine was formed. The α- and β-anomers were separated by semipreparative hplc on a LICHROSORB 10 DIOL column. The β-anomer had no antiviral activity, but it had modest cytostatic activity against tumor cells. 相似文献
18.
Krzysztof Dziewiszek Raymond F. Schinazi Ting-Chao Chou Tsann-Long Su Jolanta M. Dzik Wojciech Rode 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):77-94
Abstract A number of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)uracil and -cytosine nucleosides substituted at the 5 position with a nitrophenyl or nitrobenzyl group were synthesized from 5-phenyl- and 5-benzyluracil via condensation of the fluorinated sugar, followed by nitration. The corresponding amino analogues were also prepared by reduction of the nitro nucleosides. The uracil nucleosides were converted into the corresponding cytosine nucleosides by way of the triazole intermediates. None of these nucleosides exhibited significant activity against herpes simplex virus type 1 in Vero cells. However, cytosine nucleosides containing the o-nitrophenyl, p-nitrophenyl, p-nitrobenzyl or p-aminobenzyl substituent were found to be toxic (even at 1 μM) to uninfected Vero cells, although they were essentially nontoxic in HL-60 cells. The 5′-monophosphates of the uracil nucleosides were inhibitors of the reaction catalyzed by purified Ehrlich ascites carcinoma thymidylate synthase, the 5-phenyluracil nucleotides causing a strong inhibition, competitive vs dUMP, described by the Ki value of 0.01 μM. 相似文献
19.
Hiroshi Satoh Yuichi Yoshimura Mikari Watanabe Noriyuki Ashida Katsushi Ijichi Shinji Sakata 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):65-79
Abstract Various 5-substituted 1-(2-deoxy-2-C-methylene-4-thio-β-D-erythropentofuranosyl)uracils (4′-thioDMDUs) were synthesized from D-glucose via sila-Pummerer-type glycosylation. All of the β-anomers of 5-substituted 4′-thioDMDU, except the 5-hydroxyethyl derivative, showed potent anti-HSV-1 activity (ED50 = 0.016–0.096 μg/mL). 5-Ethyl- and 5-iodo-4′-thioDMDUs were also active against HSV-2 (ED50 = 0.17 and 0.86 μg/mL, respectively). 5-Bromovinyl-4′-thioDMDU was particularly active against VZV (ED50 = 0.013 μg/mL). 相似文献
20.
The RGD (Arg-Gly-Asp) binding integrins α(v)β(3) and α(IIb)β(3) are integral components of various pathological and physiological processes, including tumor angiogenesis, osteoclast function, and thrombus formation. Because of this, there is interest in identifying novel compounds and proteins binding to these receptors as well as investigating the mechanism of these interactions. In this article, we describe the development and validation of competition binding assays for determining the affinity of test compounds to α(v)β(3) and α(IIb)β(3) integrin. Assays were successfully developed for each receptor, and the affinity of known compounds was comparable to published results. However, the inability of binding between α(IIb)β(3) integrin and the labeled echistatin protein ligand to reach equilibrium resulted in an assay that did not meet the assumptions of the competition binding model. Nevertheless, there was good agreement between this assay and known literature values, and intra- and interassay variability was acceptable. Binding by conformation-specific antibodies provided evidence that solid-phase bound α(IIb)β(3) receptor was in an activated conformation. This study also demonstrated that current models and methods for determining receptor affinity are simplistic and fail to account for common receptor-ligand interactions such as nondissociable interactions and varying receptor activation states. 相似文献