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Hansulrich Schmincke - One of the best experts on this subject based on the ideXlab platform.
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boundary conditions for damming of a large river by fallout during the 12 900 bp plinian laacher see eruption germany syn eruptive rhine damming ii
Journal of Volcanology and Geothermal Research, 2020Co-Authors: Cornelia Park, Hansulrich SchminckeAbstract:Abstract The Rhine River (Germany) - the largest river in Western Europe - was dammed by pyroclastic material multiple times during the major Plinian Laacher See Eruption (12,900 BP). Dams formed both upstream and downstream of the broad tectonic Lower Neuwied Basin (LNB) which interrupts the narrow Rhine canyon. Here we document upstream damming of the Rhine River at the entrance to the LNB close to the present city of Koblenz due to overloading with tephra fall into the Rhine and its major tributaries, the Moselle and the Lahn. The dam was formed repeatedly during rapid pumiceous tephra fall events and breached during breaks in eruptive activity, causing extensive, high-energy flooding throughout the entire basin. The ephemeral Koblenz dams differed significantly from “normal” volcanically-induced dams by consisting principally of washed-together pumice clasts and some driftwood. The porous nature of pumice and its ability to absorb water were crucial factors. Thus, a large volume percentage of the tephra that had fallen into the Rhine floated submerged within the upper part of the water column or swam at the surface. Moreover, the absorption of the river water by the pumice clasts increased the sediment:water ratio of the two-phase flow considerably. We here present a model of dam formation resembling the formation of ice jams. We visualize the Koblenz dams to have been elongate, partly floating and partly grounded, permeable plugs many kilometers long and rising no higher than the flood plain. Damming was most plausibly initiated in the LNB within the area of maximum tephra loading and propagated upstream in a chain reaction comparable to the formation of traffic jams. A major dam was finally accumulated at the bottleneck entrance to the LNB, a site combining several favorable conditions: the upstream multi-channel Rhine was confined to a single channel, change of flow direction by 125°, extremely low gradient (0.19‰) starting already 24 km upstream of the bottleneck, constant decrease of flow velocity over many kilometers towards the bottleneck and the Moselle River - largest tributary of the Rhine within the LNB and an important conveyor of additional tephra masses – entered the Rhine only 700 m upstream of the bottleneck. We assume that the Koblenz dams could only have formed and been stabilized by an extremely long “foot region” that extended many kilometers downstream and that was possibly connected to one or several low-rise secondary jams/dams. The backwater of Lake Brohl that was dammed by pyroclastic flows 7 km downstream of the LNB about halfway through the eruption extended further and further upstream into the LNB during the second Plinian stage of the Laacher See Eruption and was probably a major factor contributing to the formation and large size of Koblenz Dam No.4. The Koblenz dams were probably not completely sealed most of the time. This way the major pre-eruptive Rhine channel received some water. An equilibrium condition was established that enabled the dams to remain stable as long as tephra fell into the Rhine relatively continuously.
Alice L. Rodriguez - One of the best experts on this subject based on the ideXlab platform.
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synthesis and pharmacological evaluation of bivalent tethered ligands to target the mglu2 4 heterodimeric receptor results in a compound with mglu2 2 homodimer selectivity
Bioorganic & Medicinal Chemistry Letters, 2020Co-Authors: Mark G Fulton, Jeffrey P Conn, Colleen M Niswender, Alice L. Rodriguez, Matthew T. Loch, Jonathan A Javitch, Craig W LindsleyAbstract:Abstract This Letter details our ongoing efforts to develop selective positive allosteric modulators (PAMs) of the mGlu2/4 heterodimeric receptor that exists in the CNS and may represent a novel drug target to modulate the glutamatergic system. As multiple hit-to-lead campaigns from HTS hits failed to produce selective small molecule mGlu2/4 heterodimer PAMs, we were inspired by the work of Portoghese to synthesize and evaluate a set of nine bivalent tethered ligands (possessing an mGlu2 PAM at one terminus and an mGlu4 PAM at the other). Utilizing G protein-Inwardly Rectifying Potassium (GIRK) channel functional assays, we found that the tethered ligands displayed PAM activity in a cell line co-expressing both mGlu2 and mGlu4 but also in cells expressing mGlu2 or mGlu4 alone. In a CODA-RET assay, one of the tethered ligands potentiated mGlu2/4 heterodimers; however, another compound displayed 75-fold preference for the mGlu2/2 homodimer over heterodimeric mGlu2/4 or homomeric mGlu4/4. This work highlights the development of mGlu receptor PAMs with homodimer/heterodimer preference and expands the potential for PAMs as tethered ligands beyond the more classical antagonists and NAMs.
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development and antiparkinsonian activity of vu0418506 a selective positive allosteric modulator of metabotropic glutamate receptor 4 homomers without activity at mglu2 4 heteromers
ACS Chemical Neuroscience, 2016Co-Authors: Colleen M Niswender, Carrie K Jones, Analisa Thompson Gray, Scott J Daniels, Darren W Engers, Michael Bubser, Anna L. Blobaum, Alice L. Rodriguez, Matthew T. Loch, Craig W LindsleyAbstract:Metabotropic glutamate receptor 4 (mGlu4) is emerging as a potential therapeutic target for numerous central nervous system indications, including Parkinson’s disease (PD). As the glutamate binding sites among the eight mGlu receptors are highly conserved, modulation of receptor activity via allosteric sites within the receptor transmembrane domains using positive and negative allosteric modulators (PAMs and NAMs, respectively) has become a common strategy. We and others have used PAMs targeting mGlu4 to show that potentiation of receptor signaling induces antiparkinsonian activity in a variety of PD animal models, including haloperidol-induced catalepsy and 6-hydroxydopamine-induced lesion. Recently, mGlu4 has been reported to form heteromeric complexes with other mGlu receptor subtypes, such as mGlu2, and the resulting heteromer exhibits a distinct pharmacological profile in response to allosteric modulators. For example, some mGlu4 PAMs do not appear to potentiate glutamate activity when mGlu2 and mGlu...
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investigating metabotropic glutamate receptor 5 allosteric modulator cooperativity affinity and agonism enriching structure function studies and structure activity relationships
Molecular Pharmacology, 2012Co-Authors: Karen J Gregory, Alice L. Rodriguez, Ya Zhou, Paige N Vinson, Meredith J Noetzel, Jerri M Rook, Shaun R Stauffer, Kyle A Emmitte, Aspen Chun, Andrew S FeltsAbstract:Drug discovery programs increasingly are focusing on allosteric modulators as a means to modify the activity of G protein-coupled receptor (GPCR) targets. Allosteric binding sites are topographically distinct from the endogenous ligand (orthosteric) binding site, which allows for co-occupation of a single receptor with the endogenous ligand and an allosteric modulator that can alter receptor pharmacological characteristics. Negative allosteric modulators (NAMs) inhibit and positive allosteric modulators (PAMs) enhance the affinity and/or efficacy of orthosteric agonists. Established approaches for estimation of affinity and efficacy values for orthosteric ligands are not appropriate for allosteric modulators, and this presents challenges for fully understanding the actions of novel modulators of GPCRs. Metabotropic glutamate receptor 5 (mGlu5) is a family C GPCR for which a large array of allosteric modulators have been identified. We took advantage of the many tools for probing allosteric sites on mGlu5 to validate an operational model of allosterism that allows quantitative estimation of modulator affinity and cooperativity values. Affinity estimates derived from functional assays fit well with affinities measured in radioligand binding experiments for both PAMs and NAMs with diverse chemical scaffolds and varying degrees of cooperativity. We observed modulation bias for PAMs when we compared mGlu5-mediated Ca2+ mobilization and extracellular signal-regulated kinase 1/2 phosphorylation data. Furthermore, we used this model to quantify the effects of mutations that reduce binding or potentiation by PAMs. This model can be applied to PAM and NAM potency curves in combination with maximal fold-shift data to derive reliable estimates of modulator affinities.
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discovery of molecular switches within the adx 47273 mglu5 pam scaffold that modulate modes of pharmacology to afford potent mglu5 nams pams and partial antagonists
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Jeffrey P Lamb, Darren W Engers, Colleen M Niswender, Alice L. Rodriguez, Daryl F Venable, Jeffrey P ConnAbstract:This Letter describes a chemical lead optimization campaign directed at a weak mGlu5 NAM discovered while developing SAR for the mGlu5 PAM, ADX-47273. An iterative parallel synthesis effort discovered multiple, subtle molecular switches that afford potent mGlu5 NAMs, mGlu5 PAMs as well as mGlu5 partial antagonists.
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discovery and sar of novel mglur5 non competitive antagonists not based on an mpep chemotype
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Alice L. Rodriguez, Stacey R Lindsley, Uyen M Le, Ya Zhou, Richard Williams, Mark D GrierAbstract:Abstract This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and the first example of a mode of pharmacology ‘switch’ to provide PAMs with a non-MPEP scaffold.
Craig W Lindsley - One of the best experts on this subject based on the ideXlab platform.
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synthesis and pharmacological evaluation of bivalent tethered ligands to target the mglu2 4 heterodimeric receptor results in a compound with mglu2 2 homodimer selectivity
Bioorganic & Medicinal Chemistry Letters, 2020Co-Authors: Mark G Fulton, Jeffrey P Conn, Colleen M Niswender, Alice L. Rodriguez, Matthew T. Loch, Jonathan A Javitch, Craig W LindsleyAbstract:Abstract This Letter details our ongoing efforts to develop selective positive allosteric modulators (PAMs) of the mGlu2/4 heterodimeric receptor that exists in the CNS and may represent a novel drug target to modulate the glutamatergic system. As multiple hit-to-lead campaigns from HTS hits failed to produce selective small molecule mGlu2/4 heterodimer PAMs, we were inspired by the work of Portoghese to synthesize and evaluate a set of nine bivalent tethered ligands (possessing an mGlu2 PAM at one terminus and an mGlu4 PAM at the other). Utilizing G protein-Inwardly Rectifying Potassium (GIRK) channel functional assays, we found that the tethered ligands displayed PAM activity in a cell line co-expressing both mGlu2 and mGlu4 but also in cells expressing mGlu2 or mGlu4 alone. In a CODA-RET assay, one of the tethered ligands potentiated mGlu2/4 heterodimers; however, another compound displayed 75-fold preference for the mGlu2/2 homodimer over heterodimeric mGlu2/4 or homomeric mGlu4/4. This work highlights the development of mGlu receptor PAMs with homodimer/heterodimer preference and expands the potential for PAMs as tethered ligands beyond the more classical antagonists and NAMs.
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development and antiparkinsonian activity of vu0418506 a selective positive allosteric modulator of metabotropic glutamate receptor 4 homomers without activity at mglu2 4 heteromers
ACS Chemical Neuroscience, 2016Co-Authors: Colleen M Niswender, Carrie K Jones, Analisa Thompson Gray, Scott J Daniels, Darren W Engers, Michael Bubser, Anna L. Blobaum, Alice L. Rodriguez, Matthew T. Loch, Craig W LindsleyAbstract:Metabotropic glutamate receptor 4 (mGlu4) is emerging as a potential therapeutic target for numerous central nervous system indications, including Parkinson’s disease (PD). As the glutamate binding sites among the eight mGlu receptors are highly conserved, modulation of receptor activity via allosteric sites within the receptor transmembrane domains using positive and negative allosteric modulators (PAMs and NAMs, respectively) has become a common strategy. We and others have used PAMs targeting mGlu4 to show that potentiation of receptor signaling induces antiparkinsonian activity in a variety of PD animal models, including haloperidol-induced catalepsy and 6-hydroxydopamine-induced lesion. Recently, mGlu4 has been reported to form heteromeric complexes with other mGlu receptor subtypes, such as mGlu2, and the resulting heteromer exhibits a distinct pharmacological profile in response to allosteric modulators. For example, some mGlu4 PAMs do not appear to potentiate glutamate activity when mGlu2 and mGlu...
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probing the metabotropic glutamate receptor 5 mglu5 positive allosteric modulator pam binding pocket discovery of point mutations that engender a molecular switch in pam pharmacology
Molecular Pharmacology, 2013Co-Authors: Karen J Gregory, Craig W Lindsley, Shaun R Stauffer, Elizabeth Nguyen, Sean D Reiff, Emma F Squire, Jens Meiler, Jeffrey P ConnAbstract:Positive allosteric modulation of metabotropic glutamate receptor subtype 5 (mGlu5) is a promising novel approach for the treatment of schizophrenia and cognitive disorders. Allosteric binding sites are topographically distinct from the endogenous ligand (orthosteric) binding site, allowing for co-occupation of a single receptor with the endogenous ligand and an allosteric modulator. Negative allosteric modulators (NAMs) inhibit and positive allosteric modulators (PAMs) enhance the affinity and/or efficacy of the orthosteric agonist. The molecular determinants that govern mGlu5 modulator affinity versus cooperativity are not well understood. Focusing on the modulators based on the acetylene scaffold, we sought to determine the molecular interactions that contribute to PAM versus NAM pharmacology. Generation of a comparative model of the transmembrane-spanning region of mGlu5 served as a tool to predict and interpret the impact of mutations in this region. Application of an operational model of allosterism allowed for determination of PAM and NAM affinity estimates at receptor constructs that possessed no detectable radioligand binding as well as delineation of effects on affinity versus cooperativity. Novel mutations within the transmembrane domain (TM) regions were identified that had differential effects on acetylene PAMs versus 2-methyl-6-(phenylethynyl)-pyridine, a prototypical NAM. Three conserved amino acids (Y658, T780, and S808) and two nonconserved residues (P654 and A809) were identified as key determinants of PAM activity. Interestingly, we identified two point mutations in TMs 6 and 7 that, when mutated, engender a mode switch in the pharmacology of certain PAMs.
Karen J Gregory - One of the best experts on this subject based on the ideXlab platform.
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probing the metabotropic glutamate receptor 5 mglu5 positive allosteric modulator pam binding pocket discovery of point mutations that engender a molecular switch in pam pharmacology
Molecular Pharmacology, 2013Co-Authors: Karen J Gregory, Craig W Lindsley, Shaun R Stauffer, Elizabeth Nguyen, Sean D Reiff, Emma F Squire, Jens Meiler, Jeffrey P ConnAbstract:Positive allosteric modulation of metabotropic glutamate receptor subtype 5 (mGlu5) is a promising novel approach for the treatment of schizophrenia and cognitive disorders. Allosteric binding sites are topographically distinct from the endogenous ligand (orthosteric) binding site, allowing for co-occupation of a single receptor with the endogenous ligand and an allosteric modulator. Negative allosteric modulators (NAMs) inhibit and positive allosteric modulators (PAMs) enhance the affinity and/or efficacy of the orthosteric agonist. The molecular determinants that govern mGlu5 modulator affinity versus cooperativity are not well understood. Focusing on the modulators based on the acetylene scaffold, we sought to determine the molecular interactions that contribute to PAM versus NAM pharmacology. Generation of a comparative model of the transmembrane-spanning region of mGlu5 served as a tool to predict and interpret the impact of mutations in this region. Application of an operational model of allosterism allowed for determination of PAM and NAM affinity estimates at receptor constructs that possessed no detectable radioligand binding as well as delineation of effects on affinity versus cooperativity. Novel mutations within the transmembrane domain (TM) regions were identified that had differential effects on acetylene PAMs versus 2-methyl-6-(phenylethynyl)-pyridine, a prototypical NAM. Three conserved amino acids (Y658, T780, and S808) and two nonconserved residues (P654 and A809) were identified as key determinants of PAM activity. Interestingly, we identified two point mutations in TMs 6 and 7 that, when mutated, engender a mode switch in the pharmacology of certain PAMs.
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investigating metabotropic glutamate receptor 5 allosteric modulator cooperativity affinity and agonism enriching structure function studies and structure activity relationships
Molecular Pharmacology, 2012Co-Authors: Karen J Gregory, Alice L. Rodriguez, Ya Zhou, Paige N Vinson, Meredith J Noetzel, Jerri M Rook, Shaun R Stauffer, Kyle A Emmitte, Aspen Chun, Andrew S FeltsAbstract:Drug discovery programs increasingly are focusing on allosteric modulators as a means to modify the activity of G protein-coupled receptor (GPCR) targets. Allosteric binding sites are topographically distinct from the endogenous ligand (orthosteric) binding site, which allows for co-occupation of a single receptor with the endogenous ligand and an allosteric modulator that can alter receptor pharmacological characteristics. Negative allosteric modulators (NAMs) inhibit and positive allosteric modulators (PAMs) enhance the affinity and/or efficacy of orthosteric agonists. Established approaches for estimation of affinity and efficacy values for orthosteric ligands are not appropriate for allosteric modulators, and this presents challenges for fully understanding the actions of novel modulators of GPCRs. Metabotropic glutamate receptor 5 (mGlu5) is a family C GPCR for which a large array of allosteric modulators have been identified. We took advantage of the many tools for probing allosteric sites on mGlu5 to validate an operational model of allosterism that allows quantitative estimation of modulator affinity and cooperativity values. Affinity estimates derived from functional assays fit well with affinities measured in radioligand binding experiments for both PAMs and NAMs with diverse chemical scaffolds and varying degrees of cooperativity. We observed modulation bias for PAMs when we compared mGlu5-mediated Ca2+ mobilization and extracellular signal-regulated kinase 1/2 phosphorylation data. Furthermore, we used this model to quantify the effects of mutations that reduce binding or potentiation by PAMs. This model can be applied to PAM and NAM potency curves in combination with maximal fold-shift data to derive reliable estimates of modulator affinities.
Jeffrey P Conn - One of the best experts on this subject based on the ideXlab platform.
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synthesis and pharmacological evaluation of bivalent tethered ligands to target the mglu2 4 heterodimeric receptor results in a compound with mglu2 2 homodimer selectivity
Bioorganic & Medicinal Chemistry Letters, 2020Co-Authors: Mark G Fulton, Jeffrey P Conn, Colleen M Niswender, Alice L. Rodriguez, Matthew T. Loch, Jonathan A Javitch, Craig W LindsleyAbstract:Abstract This Letter details our ongoing efforts to develop selective positive allosteric modulators (PAMs) of the mGlu2/4 heterodimeric receptor that exists in the CNS and may represent a novel drug target to modulate the glutamatergic system. As multiple hit-to-lead campaigns from HTS hits failed to produce selective small molecule mGlu2/4 heterodimer PAMs, we were inspired by the work of Portoghese to synthesize and evaluate a set of nine bivalent tethered ligands (possessing an mGlu2 PAM at one terminus and an mGlu4 PAM at the other). Utilizing G protein-Inwardly Rectifying Potassium (GIRK) channel functional assays, we found that the tethered ligands displayed PAM activity in a cell line co-expressing both mGlu2 and mGlu4 but also in cells expressing mGlu2 or mGlu4 alone. In a CODA-RET assay, one of the tethered ligands potentiated mGlu2/4 heterodimers; however, another compound displayed 75-fold preference for the mGlu2/2 homodimer over heterodimeric mGlu2/4 or homomeric mGlu4/4. This work highlights the development of mGlu receptor PAMs with homodimer/heterodimer preference and expands the potential for PAMs as tethered ligands beyond the more classical antagonists and NAMs.
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probing the metabotropic glutamate receptor 5 mglu5 positive allosteric modulator pam binding pocket discovery of point mutations that engender a molecular switch in pam pharmacology
Molecular Pharmacology, 2013Co-Authors: Karen J Gregory, Craig W Lindsley, Shaun R Stauffer, Elizabeth Nguyen, Sean D Reiff, Emma F Squire, Jens Meiler, Jeffrey P ConnAbstract:Positive allosteric modulation of metabotropic glutamate receptor subtype 5 (mGlu5) is a promising novel approach for the treatment of schizophrenia and cognitive disorders. Allosteric binding sites are topographically distinct from the endogenous ligand (orthosteric) binding site, allowing for co-occupation of a single receptor with the endogenous ligand and an allosteric modulator. Negative allosteric modulators (NAMs) inhibit and positive allosteric modulators (PAMs) enhance the affinity and/or efficacy of the orthosteric agonist. The molecular determinants that govern mGlu5 modulator affinity versus cooperativity are not well understood. Focusing on the modulators based on the acetylene scaffold, we sought to determine the molecular interactions that contribute to PAM versus NAM pharmacology. Generation of a comparative model of the transmembrane-spanning region of mGlu5 served as a tool to predict and interpret the impact of mutations in this region. Application of an operational model of allosterism allowed for determination of PAM and NAM affinity estimates at receptor constructs that possessed no detectable radioligand binding as well as delineation of effects on affinity versus cooperativity. Novel mutations within the transmembrane domain (TM) regions were identified that had differential effects on acetylene PAMs versus 2-methyl-6-(phenylethynyl)-pyridine, a prototypical NAM. Three conserved amino acids (Y658, T780, and S808) and two nonconserved residues (P654 and A809) were identified as key determinants of PAM activity. Interestingly, we identified two point mutations in TMs 6 and 7 that, when mutated, engender a mode switch in the pharmacology of certain PAMs.
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discovery of molecular switches within the adx 47273 mglu5 pam scaffold that modulate modes of pharmacology to afford potent mglu5 nams pams and partial antagonists
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Jeffrey P Lamb, Darren W Engers, Colleen M Niswender, Alice L. Rodriguez, Daryl F Venable, Jeffrey P ConnAbstract:This Letter describes a chemical lead optimization campaign directed at a weak mGlu5 NAM discovered while developing SAR for the mGlu5 PAM, ADX-47273. An iterative parallel synthesis effort discovered multiple, subtle molecular switches that afford potent mGlu5 NAMs, mGlu5 PAMs as well as mGlu5 partial antagonists.
