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Clickable Photoaffinity Ligands for Metabotropic Glutamate Receptor 5 Based on Select Acetylenic Negative Allosteric Modulators.
Gregory KJ, Velagaleti R, Thal DM, Brady RM, Christopoulos A, Conn PJ, Lapinsky DJ
(2016) ACS Chem Biol 11: 1870-9
MeSH Terms: Acetylene, Allosteric Regulation, Click Chemistry, HEK293 Cells, Humans, Ligands, Photoaffinity Labels, Radioligand Assay, Receptor, Metabotropic Glutamate 5
Show Abstract · Added April 6, 2017
G protein-coupled receptors (GPCRs) represent the largest class of current drug targets. In particular, small-molecule allosteric modulators offer substantial potential for selectively "tuning" GPCR activity. However, there remains a critical need for experimental strategies that unambiguously determine direct allosteric ligand-GPCR interactions, to facilitate both chemical biology studies and rational structure-based drug design. We now report the development and use of first-in-class clickable allosteric photoprobes for a GPCR based on metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulator (NAM) chemotypes. Select acetylenic mGlu5 NAM lead compounds were rationally modified to contain either a benzophenone or an aryl azide as a photoreactive functional group, enabling irreversible covalent attachment to mGlu5 via photoactivation. Additionally, a terminal alkyne or an aliphatic azide was incorporated as a click chemistry handle, allowing chemoselective attachment of fluorescent moieties to the irreversibly mGlu5-bound probe via tandem photoaffinity labeling-bioorthogonal conjugation. These clickable photoprobes retained submicromolar affinity for mGlu5 and negative cooperativity with glutamate, interacted with the "common allosteric-binding site," displayed slow binding kinetics, and could irreversibly label mGlu5 following UV exposure. We depleted the number of functional mGlu5 receptors using an irreversibly bound NAM to elucidate and delineate orthosteric agonist affinity and efficacy. Finally, successful conjugation of fluorescent dyes via click chemistry was demonstrated for each photoprobe. In the future, these clickable photoprobes are expected to aid our understanding of the structural basis of mGlu5 allosteric modulation. Furthermore, tandem photoaffinity labeling-bioorthogonal conjugation is expected to be a broadly applicable experimental strategy across the entire GPCR superfamily.
0 Communities
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9 MeSH Terms
Exploration of allosteric agonism structure-activity relationships within an acetylene series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs): discovery of 5-((3-fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254).
Turlington M, Noetzel MJ, Chun A, Zhou Y, Gogliotti RD, Nguyen ED, Gregory KJ, Vinson PN, Rook JM, Gogi KK, Xiang Z, Bridges TM, Daniels JS, Jones C, Niswender CM, Meiler J, Conn PJ, Lindsley CW, Stauffer SR
(2013) J Med Chem 56: 7976-96
MeSH Terms: Acetylene, Allosteric Regulation, Amides, Animals, Binding, Competitive, Cell Membrane, Drug Discovery, Excitatory Postsynaptic Potentials, HEK293 Cells, Hippocampus, Humans, Male, Models, Chemical, Models, Molecular, Molecular Structure, Picolinic Acids, Protein Structure, Tertiary, Radioligand Assay, Rats, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5, Structure-Activity Relationship
Show Abstract · Added January 24, 2015
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Both allosteric agonism and high glutamate fold-shift have been implicated in the neurotoxic profile of some mGlu5 PAMs; however, these hypotheses remain to be adequately addressed. To develop tool compounds to probe these hypotheses, the structure-activity relationship of allosteric agonism was examined within an acetylenic series of mGlu5 PAMs exhibiting allosteric agonism in addition to positive allosteric modulation (ago-PAMs). PAM 38t, a low glutamate fold-shift allosteric ligand (maximum fold-shift ~ 3.0), was selected as a potent PAM with no agonism in the in vitro system used for compound characterization and in two native electrophysiological systems using rat hippocampal slices. PAM 38t (ML254) will be useful to probe the relative contribution of cooperativity and allosteric agonism to the adverse effect liability and neurotoxicity associated with this class of mGlu5 PAMs.
1 Communities
4 Members
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22 MeSH Terms
Potent mGluR5 antagonists: pyridyl and thiazolyl-ethynyl-3,5-disubstituted-phenyl series.
Alagille D, DaCosta H, Chen Y, Hemstapat K, Rodriguez A, Baldwin RM, Conn PJ, Conn JP, Tamagnan GD
(2011) Bioorg Med Chem Lett 21: 3243-7
MeSH Terms: Acetylene, Animals, Binding, Competitive, Cells, Cultured, Ligands, Mice, Molecular Structure, Pyridines, Rats, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate, Structure-Activity Relationship, Thiazoles
Show Abstract · Added February 19, 2015
We report the synthesis of four series of 3,5-disubstituted-phenyl ligands targeting the metabotropic glutamate receptor subtype 5: (2-methylthiazol-4-yl)ethynyl (1a-j,), (6-methylpyridin-2-yl)ethynyl (2a-j), (5-methylpyridin-2-yl)ethynyl (3a-j,), and (pyridin-2-yl)ethynyl (4a-j,). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro assay. All compounds were found to be full antagonists and exhibited low nanomolar to subnanomolar activity.
Copyright © 2011 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
Discovery of a new class of selective cyclooxygenase-2 (COX-2) inhibitor that covalently modifies the isozyme.
Kalgutkar AS, Crews BC, Rowlinson SW, Garner C, Marnett LJ
(1999) Adv Exp Med Biol 469: 139-43
MeSH Terms: Acetylene, Alkynes, Animals, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Catalytic Domain, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors, Humans, In Vitro Techniques, Isoenzymes, Mass Spectrometry, Membrane Proteins, Prostaglandin-Endoperoxide Synthases, Sheep, Structure-Activity Relationship, Sulfides
Added March 5, 2014
0 Communities
1 Members
0 Resources
18 MeSH Terms
Covalent modification of cyclooxygenase-2 (COX-2) by 2-acetoxyphenyl alkyl sulfides, a new class of selective COX-2 inactivators.
Kalgutkar AS, Kozak KR, Crews BC, Hochgesang GP, Marnett LJ
(1998) J Med Chem 41: 4800-18
MeSH Terms: Acetylation, Acetylene, Alkynes, Animals, Anti-Inflammatory Agents, Non-Steroidal, Antineoplastic Agents, Colonic Neoplasms, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors, Dinoprostone, Exudates and Transudates, Humans, In Vitro Techniques, Inhibitory Concentration 50, Isoenzymes, Kinetics, Macrophages, Membrane Proteins, Mice, Prostaglandin-Endoperoxide Synthases, Rats, Sheep, Structure-Activity Relationship, Sulfides, Thromboxane B2, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
All of the selective COX-2 inhibitors described to date inhibit the isoform by binding tightly but noncovalently at the substrate binding site. Recently, we reported the first account of selective covalent modification of COX-2 by a novel inactivator, 2-acetoxyphenyl hept-2-ynyl sulfide (70) (Science 1998, 280, 1268-1270). Compound 70 selectively inactivates COX-2 by acetylating the same serine residue that aspirin acetylates. This paper describes the extensive structure-activity relationship (SAR) studies on the initial lead compound 2-acetoxyphenyl methyl sulfide (36) that led to the discovery of 70. Extension of the S-alkyl chain in 36 with higher alkyl homologues led to significant increases in inhibitory potency. The heptyl chain in 2-acetoxyphenyl heptyl sulfide (46) was optimum for COX-2 inhibitory potency, and introduction of a triple bond in the heptyl chain (compound 70) led to further increments in potency and selectivity. The alkynyl analogues were more potent and selective COX-2 inhibitors than the corresponding alkyl homologues. Sulfides were more potent and selective COX-2 inhibitors than the corresponding sulfoxides or sulfones or other heteroatom-containing compounds. In addition to inhibiting purified COX-2, 36, 46, and 70 also inhibited COX-2 activity in murine macrophages. Analogue 36 which displayed moderate potency and selectivity against purified human COX-2 was a potent inhibitor of COX-2 activity in the mouse macrophages. Tryptic digestion and peptide mapping of COX-2 reacted with [1-14C-acetyl]-36 indicated that selective COX-2 inhibition by 36 also resulted in the acetylation of Ser516. That COX-2 inhibition by aspirin resulted from the acetylation of Ser516 was confirmed by tryptic digestion and peptide mapping of COX-2 labeled with [1-14C-acetyl]salicyclic acid. The efficacy of the sulfides in inhibiting COX-2 activity in inflammatory cells, our recent results on the selectivity of 70 in attenuating growth of COX-2-expressing colon cancer cells, and its selectivity for inhibition of COX-2 over COX-1 in vivo indicate that this novel class of covalent modifiers may serve as potential therapeutic agents in inflammatory and proliferative disorders.
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1 Members
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27 MeSH Terms
Aspirin-like molecules that covalently inactivate cyclooxygenase-2.
Kalgutkar AS, Crews BC, Rowlinson SW, Garner C, Seibert K, Marnett LJ
(1998) Science 280: 1268-70
MeSH Terms: Acetylation, Acetylene, Alkynes, Animals, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Binding Sites, Cell Division, Cell Line, Colonic Neoplasms, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors, Dinoprostone, Drug Design, Humans, Indomethacin, Isoenzymes, Macrophages, Membrane Proteins, Mutagenesis, Site-Directed, Prostaglandin D2, Prostaglandin-Endoperoxide Synthases, Rats, Rats, Inbred Lew, Sulfides, Thromboxane B2, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
Many of aspirin's therapeutic effects arise from its acetylation of cyclooxygenase-2 (COX-2), whereas its antithrombotic and ulcerogenic effects result from its acetylation of COX-1. Here, aspirin-like molecules were designed that preferentially acetylate and irreversibly inactivate COX-2. The most potent of these compounds was o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS). Relative to aspirin, APHS was 60 times as reactive against COX-2 and 100 times as selective for its inhibition; it also inhibited COX-2 in cultured macrophages and colon cancer cells and in the rat air pouch in vivo. Such compounds may lead to the development of aspirin-like drugs for the treatment or prevention of immunological and proliferative diseases without gastrointestinal or hematologic side effects.
0 Communities
1 Members
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28 MeSH Terms
Mechanisms of cytochrome P-450 catalysis.
Guengerich FP, MacDonald TL
(1990) FASEB J 4: 2453-9
MeSH Terms: Acetylene, Alkanes, Alkenes, Animals, Catalysis, Cytochrome P-450 Enzyme System, Electrons, Hydroxylation, Models, Chemical, Oxidation-Reduction, Oxygen
Show Abstract · Added March 5, 2014
Cytochrome P-450 (P-450) enzymes catalyze the oxidation of a wide variety of substrates. Although a large number of P-450s have been characterized in different species and tissues, the mechanisms of catalysis of oxygenation may be understood in terms of a few basic principles. The chemistry is dominated by the ability of a high-valent formal (FeO)3+ species to carry out one-electron oxidations through the abstraction of hydrogen atoms, abstraction of electrons in n or pi orbitals, or the addition to pi bonds. A series of radical recombination reactions then completes the oxidation process. The protein structures are postulated to provide the axial thiolate ligand to the heme, to control the juxtaposition of the substrate (and therefore the regio- and stereoselectivity of oxidation), to alter the effective oxidation potential of the (FeO)3+ complex, and possibly to participate in specific acid/base catalysis in the oxidation of some substrates.
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1 Members
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11 MeSH Terms