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Sign Inversion in Photopharmacology: Incorporation of Cyclic Azobenzenes in Photoswitchable Potassium Channel Blockers and Openers.
Trads JB, Hüll K, Matsuura BS, Laprell L, Fehrentz T, Görldt N, Kozek KA, Weaver CD, Klöcker N, Barber DM, Trauner D
(2019) Angew Chem Int Ed Engl 58: 15421-15428
MeSH Terms: Action Potentials, Azo Compounds, Cyclization, Drug Design, G Protein-Coupled Inwardly-Rectifying Potassium Channels, HEK293 Cells, Humans, Isomerism, Lidocaine, Light, Patch-Clamp Techniques, Potassium Channel Blockers, Thermodynamics
Show Abstract · Added March 27, 2020
Photopharmacology relies on ligands that change their pharmacodynamics upon photoisomerization. Many of these ligands are azobenzenes that are thermodynamically more stable in their elongated trans-configuration. Often, they are biologically active in this form and lose activity upon irradiation and photoisomerization to their cis-isomer. Recently, cyclic azobenzenes, so-called diazocines, have emerged, which are thermodynamically more stable in their bent cis-form. Incorporation of these switches into a variety of photopharmaceuticals could convert dark-active ligands into dark-inactive ligands, which is preferred in most biological applications. This "pharmacological sign-inversion" is demonstrated for a photochromic blocker of voltage-gated potassium channels, termed CAL, and a photochromic opener of G protein-coupled inwardly rectifying potassium (GIRK) channels, termed CLOGO.
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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13 MeSH Terms
Further exploration of an N-aryl phenoxyethoxy pyridinone-based series of mGlu NAMs: Challenging SAR, enantiospecific activity and in vivo efficacy.
Yamada Y, Yohn SE, Gilliland K, Loch MT, Schulte ML, Rodriguez AL, Blobaum AL, Niswender CM, Conn PJ, Lindsley CW
(2019) Bioorg Med Chem Lett 29: 2670-2674
MeSH Terms: Animals, Anti-Anxiety Agents, Antidepressive Agents, Dose-Response Relationship, Drug, Mice, Molecular Structure, Pyridones, Rats, Receptors, Metabotropic Glutamate, Stereoisomerism, Structure-Activity Relationship
Show Abstract · Added March 3, 2020
This letter describes the further optimization of a series of mGlu NAMs based on an N-aryl phenoxyethoxy pyridinone core. A multidimensional optimization campaign, with focused matrix libraries, quickly established challenging SAR, enantiospecific activity, differences in assay read-outs (Ca flux via a promiscuous G protein (G) versus native coupling to GIRK channels), identified both full and partial mGlu NAMs and a new in vivo tool compound, VU6017587. This mGlu NAM showed efficacy in tail suspension, elevated zero maze and marble burying, suggesting selective inhibition of mGlu affords anxiolytic-like and antidepressant-like phenotypes in mice.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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11 MeSH Terms
Isomeric and Conformational Analysis of Small Drug and Drug-Like Molecules by Ion Mobility-Mass Spectrometry (IM-MS).
Phillips ST, Dodds JN, May JC, McLean JA
(2019) Methods Mol Biol 1939: 161-178
MeSH Terms: Algorithms, Amino Acids, Carbohydrates, Ion Mobility Spectrometry, Isomerism, Mass Spectrometry, Molecular Conformation, Pharmaceutical Preparations, Small Molecule Libraries, Software
Show Abstract · Added August 7, 2019
This chapter provides a broad overview of ion mobility-mass spectrometry (IM-MS) and its applications in separation science, with a focus on pharmaceutical applications. A general overview of fundamental ion mobility (IM) theory is provided with descriptions of several contemporary instrument platforms which are available commercially (i.e., drift tube and traveling wave IM). Recent applications of IM-MS toward the evaluation of structural isomers are highlighted and placed in the context of both a separation and characterization perspective. We conclude this chapter with a guided reference protocol for obtaining routine IM-MS spectra on a commercially available uniform-field IM-MS.
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Absolute Configurations of Naturally Occurring [5]- and [3]-Ladderanoic Acids: Isolation, Chiroptical Spectroscopy, and Crystallography.
Raghavan V, Johnson JL, Stec DF, Song B, Zajac G, Baranska M, Harris CM, Schley ND, Polavarapu PL, Harris TM
(2018) J Nat Prod 81: 2654-2666
MeSH Terms: Biomass, Bioreactors, Circular Dichroism, Crystallography, X-Ray, Esters, Lipids, Molecular Conformation, Molecular Structure, Spectrum Analysis, Raman, Stereoisomerism
Show Abstract · Added March 3, 2020
We have isolated mixtures of [5]- and [3]-ladderanoic acids 1a and 2a from the biomass of an anammox bioreactor and have separated the acids and their phenacyl esters for the first time by HPLC. The absolute configurations of the naturally occurring acids and their phenacyl esters are assigned as R at the site of side-chain attachment by comparison of experimental specific rotations with corresponding values predicted using quantum chemical (QC) methods. The absolute configurations for 1a and 2a were independently verified by comparison of experimental Raman optical activity spectra with corresponding spectra predicted using QC methods. The configurational assignments of 1a and 2a and of the phenacyl ester of 1a were also confirmed by X-ray crystallography.
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Structural Characterization of Methylenedianiline Regioisomers by Ion Mobility-Mass Spectrometry and Tandem Mass Spectrometry. 4. 3-Ring and 4-Ring Isomers.
Crescentini TM, Stow SM, Forsythe JG, May JC, McLean JA, Hercules DM
(2018) Anal Chem 90: 14453-14461
MeSH Terms: Aniline Compounds, Ion Mobility Spectrometry, Stereoisomerism, Tandem Mass Spectrometry
Show Abstract · Added December 17, 2018
Matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) is used to characterize methylenedianiline (MDA) 3-ring and 4-ring species. Building on our previous MALDI-MS 2-ring MDA isomer study, here we compare 3-ring and 4-ring electrospray ionization (ESI) and MALDI results. In ESI, 3-ring and 4-ring MDAs each form a single [M + H] parent ion. However, in MALDI, each MDA multimer forms three unique precursor ions: [M + H], [M], and [M - H]. In this study, 3-ring and 4-ring MDA precursors are characterized to identify the unique fragment ions formed and their respective fragmentation pathways. In addition to the three possible precursors, the 3-ring and 4-ring species are higher-order oligomer precursors in polyurethane (PUR) production and thus provide additional insight into the polymeric behavior of these PUR hard block precursors. The combination of ion mobility-mass spectrometry (IM - MS) and tandem mass spectrometry (MS/MS) allow the structural characterization of these larger MDA multimers.
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4 MeSH Terms
Untargeted Molecular Discovery in Primary Metabolism: Collision Cross Section as a Molecular Descriptor in Ion Mobility-Mass Spectrometry.
Nichols CM, Dodds JN, Rose BS, Picache JA, Morris CB, Codreanu SG, May JC, Sherrod SD, McLean JA
(2018) Anal Chem 90: 14484-14492
MeSH Terms: Carbohydrates, Chromatography, High Pressure Liquid, Humans, Ion Mobility Spectrometry, Isomerism, Mass Spectrometry, Metabolomics
Show Abstract · Added December 17, 2018
In this work, we established a collision cross section (CCS) library of primary metabolites based on analytical standards in the Mass Spectrometry Metabolite Library of Standards (MSMLS) using a commercially available ion mobility-mass spectrometer (IM-MS). From the 554 unique compounds in the MSMLS plate library, we obtained a total of 1246 CCS measurements over a wide range of biochemical classes and adduct types. Resulting data analysis demonstrated that the curated CCS library provides broad molecular coverage of metabolic pathways and highlights intrinsic mass-mobility relationships for specific metabolite superclasses. The separation and characterization of isomeric metabolites were assessed, and all molecular species contained within the plate library, including isomers, were critically evaluated to determine the analytical separation efficiency in both the mass ( m/ z) and mobility (CCS/ΔCCS) dimension required for untargeted metabolomic analyses. To further demonstrate the analytical utility of CCS as an additional molecular descriptor, a well-characterized biological sample of human plasma serum (NIST SRM 1950) was examined by LC-IM-MS and used to provide a detailed isomeric analysis of carbohydrate constituents by ion mobility.
1 Communities
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7 MeSH Terms
Determining Double Bond Position in Lipids Using Online Ozonolysis Coupled to Liquid Chromatography and Ion Mobility-Mass Spectrometry.
Harris RA, May JC, Stinson CA, Xia Y, McLean JA
(2018) Anal Chem 90: 1915-1924
MeSH Terms: Animals, Chickens, Chromatography, Liquid, Eggs, Fatty Acids, Unsaturated, Glycerophospholipids, Isomerism, Lipids, Ozone, Spectrometry, Mass, Electrospray Ionization
Show Abstract · Added December 17, 2018
The increasing focus on lipid metabolism has revealed a need for analytical techniques capable of structurally characterizing lipids with a high degree of specificity. Lipids can exist as any one of a large number of double bond positional isomers, which are indistinguishable by single-stage mass spectrometry alone. Ozonolysis reactions coupled to mass spectrometry have previously been demonstrated as a means for localizing double bonds in unsaturated lipids. Here we describe an online, solution-phase reactor using ozone produced via a low-pressure mercury lamp, which generates aldehyde products diagnostic of cleavage at a particular double bond position. This flow-cell device is utilized in conjunction with structurally selective ion mobility-mass spectrometry. The lamp-mediated reaction was found to be effective for multiple lipid species in both positive and negative ionization modes, and the conversion efficiency from precursor to product ions was tunable across a wide range (20-95%) by varying the flow rate through the ozonolysis device. Ion mobility separation of the ozonolysis products generated additional structural information and revealed the presence of saturated species in a complex mixture. The method presented here is simple, robust, and readily coupled to existing instrument platforms with minimal modifications necessary. For these reasons, application to standard lipidomic workflows is possible and aids in more comprehensive structural characterization of a myriad of lipid species.
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10 MeSH Terms
Dual cyclooxygenase-fatty acid amide hydrolase inhibitor exploits novel binding interactions in the cyclooxygenase active site.
Goodman MC, Xu S, Rouzer CA, Banerjee S, Ghebreselasie K, Migliore M, Piomelli D, Marnett LJ
(2018) J Biol Chem 293: 3028-3038
MeSH Terms: Amidohydrolases, Catalytic Domain, Cyclooxygenase Inhibitors, Isoenzymes, Phenylcarbamates, Phenylpropionates, Prostaglandin-Endoperoxide Synthases, Protein Binding, Stereoisomerism, Substrate Specificity
Show Abstract · Added April 22, 2018
The cyclooxygenases COX-1 and COX-2 oxygenate arachidonic acid (AA) to prostaglandin H (PGH). COX-2 also oxygenates the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA) to the corresponding PGH analogs. Both enzymes are targets of nonsteroidal anti-inflammatory drugs (NSAIDs), but NSAID-mediated COX inhibition is associated with gastrointestinal toxicity. One potential strategy to counter this toxicity is to also inhibit fatty acid amide hydrolase (FAAH), which hydrolyzes bioactive fatty acid ethanolamides (FAEs) into fatty acids and ethanolamine. Here, we investigated the mechanism of COX inhibition by ARN2508, an NSAID that inhibits both COXs and FAAH with high potency, target selectivity, and decreased gastrointestinal toxicity in mouse models, presumably due to its ability to increase levels of FAEs. A 2.27-Å-resolution X-ray crystal structure of the COX-2·()-ARN2508 complex reveals that ARN2508 adopts a binding pose similar to that of its parent NSAID flurbiprofen. However, ARN2508's alkyl tail is inserted deep into the top channel, an active site region not exploited by any previously reported NSAID. As for flurbiprofen, ARN2508's potency is highly dependent on the configuration of the α-methyl group. Thus, ()-ARN2508 is more potent than ()-ARN2508 for inhibition of AA oxygenation by both COXs and 2-AG oxygenation by COX-2. Also, similarly to ()-flurbiprofen, ()-ARN2508 exhibits substrate selectivity for inhibition of 2-AG oxygenation. Site-directed mutagenesis confirms the importance of insertion of the alkyl tail into the top channel for ()-ARN2508's potency and suggests a role for Ser-530 as a determinant of the inhibitor's slow rate of inhibition compared with that of ()-flurbiprofen.
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10 MeSH Terms
Absolute configuration of an axially chiral sulfonate determined from its optical rotatory dispersion, electronic circular dichroism, and vibrational circular dichroism spectra.
Covington CL, Raghavan V, Smuts JP, Armstrong DW, Polavarapu PL
(2017) Chirality 29: 670-676
MeSH Terms: Circular Dichroism, Models, Molecular, Molecular Conformation, Naphthalenes, Optical Rotatory Dispersion, Stereoisomerism, Sulfonic Acids, Vibration
Show Abstract · Added April 10, 2018
The absolute configuration (AC) of an axially chiral sulfonate (aCSO), 3,5-dimethyl-2-(naphthalen-1-yl)-6-(naphthalen-1-yl)benzenesulfonate (labeled as aCSO5), was investigated using optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD) spectroscopies. All three methods led to the same conclusion and the AC of aCSO5 is reliably determined to be (-)-(aR, aR), or conversely (+)-(aS, aS).
© 2017 Wiley Periodicals, Inc.
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8 MeSH Terms
Structural Characterization of Methylenedianiline Regioisomers by Ion Mobility-Mass Spectrometry, Tandem Mass Spectrometry, and Computational Strategies. 3. MALDI Spectra of 2-Ring Isomers.
Stow SM, Crescentini TM, Forsythe JG, May JC, McLean JA, Hercules DM
(2017) Anal Chem 89: 9900-9910
MeSH Terms: Aniline Compounds, Density Functional Theory, Ion Mobility Spectrometry, Mass Spectrometry, Molecular Dynamics Simulation, Molecular Structure, Stereoisomerism
Show Abstract · Added December 17, 2018
Characterization of methylenedianiline (MDA) 2-ring isomers (2,2'-, 2,4'-, and 4,4'-MDA) is reported using matrix assisted laser desorption/ionization-mass spectrometry (MALDI-MS), a common technique used for characterizing synthetic polymers. MDA is a precursor to methylene diphenyl diisocyanate (MDI), a hard block component in polyurethane (PUR) synthesis. This work focuses on comparing MALDI results to those of our previous electrospray ionization-mass spectrometry (ESI-MS) studies. In ESI, 2-ring MDA isomers formed single unique [M + H] (199 Da) parent ions, whereas in MALDI each isomer shows significant formation of three precursor ions: [M - H] = 197 Da, [M] = 198 Da, and [M + H] = 199 Da. Structures and schemes are proposed for the MALDI fragment ions associated with each precursor ion. Ion mobility-mass spectrometry (IM-MS), tandem mass spectrometry (MS/MS), and computational methods were all critical in determining the structures for both precursor and fragment ions as well as the fragmentation mechanisms. The present study indicates that the [M - H] and [M] ions are formed by the MALDI process, explaining why they were not observed with ESI.
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7 MeSH Terms