The Experts below are selected from a list of 267 Experts worldwide ranked by ideXlab platform
Gerhard Rammes - One of the best experts on this subject based on the ideXlab platform.
-
the potassium Channel Modulator flupirtine shifts the frequency response function of hippocampal synapses to favour ltd in mice
Neuroscience Letters, 2004Co-Authors: Shahnaz Christina Azad, Wanda Simon, Gerhard Hapfelmeier, Walter Zieglgänsberger, Matthias Eder, Hans-ulrich Dodt, Gerhard RammesAbstract:Flupirtine is a centrally acting nonopioid analgesic with muscle-relaxant properties. Flupirtine has been found to activate inwardly rectifying potassium conductances and hence to indirectly inhibit the activation of NMDA receptors. NMDA receptor activation is crucial for the induction of long-term potentiation (LTP) of synaptic transmission, which is considered as cellular correlate of learning and memory and of central sensitization in chronic pain states. Although flupirtine has been widely used for the management of pain, its effects on synaptic plasticity have not yet been investigated. We, therefore, performed extracellular and whole-cell patch-clamp recordings in hippocampal slices of mice to examine the effects of flupirtine on synaptic plasticity and neuronal membrane properties. Excitatory postsynaptic potentials (EPSPs) in the CA1 region were evoked alternately by stimulating two independent Schaffer collateral-commissural inputs. LTP and long-term depression (LTD) were induced by different stimulation paradigms (100 Hz, 10 Hz, 5 Hz, and 1 Hz). Flupirtine (30 microM) diminished the degree of LTP and enhanced LTD. This effect is most likely due to the hyperpolarization of CA1 pyramidal neurons and the reduction of their input resistance found after application of flupirtine. The observed effects on synaptic strength could underly the beneficial effects of flupirtine on different types of chronic pain.
-
The potassium Channel Modulator flupirtine shifts the frequency-response function of hippocampal synapses to favour LTD in mice
Neuroscience Letters, 2004Co-Authors: Shahnaz Christina Azad, Wanda Simon, Gerhard Hapfelmeier, Walter Zieglgänsberger, Matthias Eder, Hans-ulrich Dodt, Gerhard RammesAbstract:Flupirtine is a centrally acting nonopioid analgesic with muscle-relaxant properties. Flupirtine has been found to activate inwardly rectifying potassium conductances and hence to indirectly inhibit the activation of NMDA receptors. NMDA receptor activation is crucial for the induction of long-term potentiation (LTP) of synaptic transmission, which is considered as cellular correlate of learning and memory and of central sensitization in chronic pain states. Although flupirtine has been widely used for the management of pain, its effects on synaptic plasticity have not yet been investigated. We, therefore, performed extracellular and whole-cell patch-clamp recordings in hippocampal slices of mice to examine the effects of flupirtine on synaptic plasticity and neuronal membrane properties. Excitatory postsynaptic potentials (EPSPs) in the CA1 region were evoked alternately by stimulating two independent Schaffer collateral-commissural inputs. LTP and long-term depression (LTD) were induced by different stimulation paradigms (100 Hz, 10 Hz, 5 Hz, and 1 Hz). Flupirtine (30 μM) diminished the degree of LTP and enhanced LTD. This effect is most likely due to the hyperpolarization of CA1 pyramidal neurons and the reduction of their input resistance found after application of flupirtine. The observed effects on synaptic strength could underly the beneficial effects of flupirtine on different types of chronic pain. © 2004 Elsevier Ireland Ltd. All rights reserved.
Ulrich Quast - One of the best experts on this subject based on the ideXlab platform.
-
atp sensitive k Channel Modulator binding to sulfonylurea receptors sur2a and sur2b opposite effects of mgadp
Molecular Pharmacology, 1999Co-Authors: Annette Hambrock, Cornelia Lofflerwalz, Doris Kloor, Ursula Delabar, Yoshiyuki Horio, Yoshihisa Kurachi, Ulrich QuastAbstract:KATP Channels are heteromeric complexes of inwardly rectifying K+ Channel subunits and sulfonylurea receptors (SURs). SUR2A and SUR2B, which differ within the carboxyl terminal exon 38, are characteristic for the cardiac and smooth muscle type Channels, respectively. Here we compare binding of the tritiated KATP Channel opener, [3H]P1075, to membranes from human embryonic kidney (HEK) cells transfected with murine SUR2A and 2B at 37°C. Binding to both SURs required addition of Mg2+ and ATP in the low micromolar range. In the presence of MgATP, micromolar concentrations of MgADP, formed by the ATPase activity of the membrane preparation, increased binding to SUR2A but inhibited binding to SUR2B. Decreasing temperatures strongly reduced [3H]P1075 binding to SUR2A, whereas binding to SUR2B was increased in a bell-shaped manner. Kinetic experiments revealed a faster dissociation of the [3H]P1075-SUR2A complex, whereas the association rate constants for [3H]P1075 binding to SUR2A and 2B were similar. Openers inhibited [3H]P1075 binding to SUR2A with potencies ≈4 times lower than to SUR2B; in contrast, glibenclamide inhibited [3H]P1075 binding to SUR2A ≈8 times more potently than to SUR2B. The data suggest that SUR2A and 2B represent the opener receptors of cardiac and vascular smooth muscle KATPChannels, respectively, and show that MgADP is an important Modulator of opener binding to SUR. The different carboxyl termini of SUR2A and 2B lead to differences in the MgADP dependence and the thermodynamics of [3H]P1075 binding, as well as in the affinities for openers and glibenclamide, underlining the importance of this part of the molecule for KATP Channel Modulator binding.
-
mg2 and atp dependence of katp Channel Modulator binding to the recombinant sulphonylurea receptor sur2b
British Journal of Pharmacology, 1998Co-Authors: Annette Hambrock, Cornelia Lofflerwalz, Yoshihisa Kurachi, Ulrich QuastAbstract:1 The binding of Modulators of the ATP-sensitive K+ Channel (KATP Channel) to the murine sulphonylurea receptor, SUR2B, was investigated. SUR2B, a proposed subunit of the vascular KATP Channel, was expressed in HEK 293 cells and binding assays were performed in membranes at 37°C using the tritiated KATP Channel opener, [3H]-P1075. 2 Binding of [3H]-P1075 required the presence of Mg2+ and ATP. MgATP activated binding with EC50 values of 10 and 3 μM at free Mg2+ concentrations of 3 μM and 1 mM, respectively. At 1 mM Mg2+, binding was lower than at 3 μM Mg2+. 3 [3H]-P1075 saturation binding experiments, performed at 3 mM ATP and free Mg2+ concentrations of 3 μM and 1 mM, gave KD values of 1.8 and 3.4 nM and BMAX values of 876 and 698 fmol mg−1, respectively. 4 In competition experiments, openers inhibited [3H]-P1075 binding with potencies similar to those determined in rings of rat aorta. 5 Glibenclamide inhibited [3H]-P1075 binding with Ki values of 0.35 and 2.4 μM at 3 μM and 1 mM free Mg2+, respectively. Glibenclamide enhanced the dissociation of the [3H]-P1075-SUR2B complex suggesting a negative allosteric coupling between the binding sites for P1075 and the sulphonylureas. 6 It is concluded that an MgATP site on SUR2B with μM affinity must be occupied to allow opener binding whereas Mg2+ concentrations 10 μM decrease the affinities for openers and glibenclamide. The properties of the [3H]-P1075 site strongly suggest that SUR2B represents the drug receptor of the openers in vascular smooth muscle. British Journal of Pharmacology (1998) 125, 577–583; doi:10.1038/sj.bjp.0702109
Lisa R. Thompson - One of the best experts on this subject based on the ideXlab platform.
-
Optimisation of Permanganate Oxidation and Suzuki−Miyaura Coupling Steps in the Synthesis of a Nav1.8 Sodium Channel Modulator
Organic Process Research & Development, 2010Co-Authors: M. Jonathan Fray, Adam T. Gillmore, Melanie S. Glossop, David J. Mcmanus, Ian B. Moses, Céline F. B. Praquin, Keith A. Reeves, Lisa R. ThompsonAbstract:The development is described of a viable kilo-scale synthesis of the Nav1.8 sodium Channel Modulator, N-methyl-6-amino-5-(2,3,5-trichlorophenyl)pyridine-2-carboxamide (PF-1247324) in five steps, starting from 6-amino-5-bromo-2-picoline, in 33% overall yield. Two key steps required significant optimisation to improve yield and reproducibility. Oxidation of 6-acetamido-5-bromo-2-methylpyridine by permanganate to give the corresponding carboxylic acid derivative was improved by adding potassium dihydrogen phosphate, which moderated the reaction mixture pH and doubled the yield. The potassium fluoride-promoted Suzuki−Miyaura coupling between 2,4,5-trichlorophenylboronic acid and methyl 6-amino-5-bromopyridine-2-carboxylate, catalysed by tri(tert-butyl)phosphinepalladium (0), proceeded reliably to completion at room temperature in high yield when water was added. Anhydrous reaction mixtures reacted much more slowly, and ‘wet’ mixtures led to significant proto-deboronation in the absence of sufficient active ca...
-
optimisation of permanganate oxidation and suzuki miyaura coupling steps in the synthesis of a nav1 8 sodium Channel Modulator
Organic Process Research & Development, 2010Co-Authors: Jonathan M Fray, Adam T. Gillmore, Melanie S. Glossop, David J. Mcmanus, Ian B. Moses, Céline F. B. Praquin, Keith Reeves, Lisa R. ThompsonAbstract:The development is described of a viable kilo-scale synthesis of the Nav1.8 sodium Channel Modulator, N-methyl-6-amino-5-(2,3,5-trichlorophenyl)pyridine-2-carboxamide (PF-1247324) in five steps, starting from 6-amino-5-bromo-2-picoline, in 33% overall yield. Two key steps required significant optimisation to improve yield and reproducibility. Oxidation of 6-acetamido-5-bromo-2-methylpyridine by permanganate to give the corresponding carboxylic acid derivative was improved by adding potassium dihydrogen phosphate, which moderated the reaction mixture pH and doubled the yield. The potassium fluoride-promoted Suzuki−Miyaura coupling between 2,4,5-trichlorophenylboronic acid and methyl 6-amino-5-bromopyridine-2-carboxylate, catalysed by tri(tert-butyl)phosphinepalladium (0), proceeded reliably to completion at room temperature in high yield when water was added. Anhydrous reaction mixtures reacted much more slowly, and ‘wet’ mixtures led to significant proto-deboronation in the absence of sufficient active ca...
Jennifer F Linden - One of the best experts on this subject based on the ideXlab platform.
-
increased spontaneous firing rates in auditory midbrain following noise exposure are specifically abolished by a kv3 Channel Modulator
Hearing Research, 2018Co-Authors: L A Anderson, Giuseppe Alvaro, Nadia Pilati, Charles H Large, Lara Li Hesse, Warren Michael Henry Bakay, David Mcalpine, Roland Schaette, Jennifer F LindenAbstract:Noise exposure has been shown to produce long-lasting increases in spontaneous activity in central auditory structures in animal models, and similar pathologies are thought to contribute to clinical phenomena such as hyperacusis or tinnitus in humans. Here we demonstrate that multi-unit spontaneous neuronal activity in the inferior colliculus (IC) of mice is significantly elevated four weeks following noise exposure at recording sites with frequency tuning within or near the noise exposure band, and this selective central auditory pathology can be normalised through administration of a novel compound that modulates activity of Kv3 voltage-gated ion Channels. The compound had no statistically significant effect on IC spontaneous activity without noise exposure, nor on thresholds or frequency tuning of tone-evoked responses either with or without noise exposure. Administration of the compound produced some reduction in the magnitude of evoked responses to a broadband noise, but unlike effects on spontaneous rates, these effects on evoked responses were not specific to recording sites with frequency tuning within the noise exposure band. Thus, the results suggest that Modulators of Kv3 Channels can selectively counteract increases in spontaneous activity in the auditory midbrain associated with noise exposure.
Steven M. Toler - One of the best experts on this subject based on the ideXlab platform.
-
clinical efficacy and tolerability of the nicotinic Channel Modulator dexmecamylamine in subjects with overactive bladder
The Journal of Urology, 2015Co-Authors: Michael B Chancellor, Eboo Versi, Chris Dvergsten, Steven M. TolerAbstract:Purpose: We evaluated the efficacy and tolerability of the nicotinic Channel Modulator dexmecamylamine for overactive bladder.Materials and Methods: This was a randomized, double-blind, placebo controlled trial in 768 randomized subjects. Those with at least a 6-month history of overactive bladder were randomized to 0.5, 1 or 2 mg dexmecamylamine or placebo in a ratio of 1:1:1:2, respectively. Subjects completed a 3-day diary before each visit associated with the 12-week treatment period. They were required to have 8 or more micturitions per day and 3 or more urinary urge incontinent episodes per day if overactive bladder wet at the end of a placebo run-in period. Co-primary end points for the study included a change from baseline 1) in micturition frequency per 24 hours at week 12 and 2) in urge urinary incontinence episodes per 24 hours at week 12. Secondary end points were voided volume, nocturia episodes, OABq (Overactive Bladder Questionnaire) and urgency questionnaire.Results: Dexmecamylamine (2 mg)...
-
Clinical Pharmacokinetics of the Nicotinic Channel Modulator Dexmecamylamine (TC-5214) in Subjects with Various Degrees of Renal Impairment
Clinical Drug Investigation, 2014Co-Authors: Sofie Alverlind, Stéphane Barassin, Per Dalén, Yan Li, Steven M. Toler, Hans Eriksson, Raj TummalaAbstract:Background and Objective Dexmecamylamine (TC-5214) is a nicotinic Channel Modulator that was evaluated as a potential adjunct treatment to an antidepressant for patients with major depressive disorder. Dexmecamylamine is almost completely eliminated via the kidneys, with more than 90 % of a given dose excreted unchanged in urine. The aim of this study was to assess the single-dose pharmacokinetics of dexmecamylamine in subjects with various degrees of renal impairment and subjects undergoing hemodialysis.
-
Population pharmacokinetics of TC‐5214, a nicotinic Channel Modulator, in phase I and II clinical studies
The Journal of Clinical Pharmacology, 2014Co-Authors: Hongmei Xu, Sofie Alverlind, Steven M. Toler, Raj Tummala, Anja Henningsson, Jessica S. Beaver, Nidal Al-hunitiAbstract:: TC-5214 (dexmecamylamine) is a nicotinic Channel Modulator that has previously been evaluated for treatment of major depression disorder (MDD) and is currently being evaluated by Targacept as a treatment for overactive bladder. A comprehensive population pharmacokinetic (POP PK) model of TC-5214 was developed using nonlinear mixed-effects modeling of pooled plasma concentration data from 6 early phase I studies in 179 healthy participants or patients with non-MDD and 1 phase II study in 68 MDD patients. Concentration-time profiles of TC-5214 after either single or multiple oral doses of TC-5214 was described by a one-compartment model with first-order absorption with lag time and first-order elimination. Covariate analysis revealed that creatinine clearance was a significant covariate on clearance and that body weight significantly influenced the central volume of distribution. The final model (with identified covariates) was used to simulate steady-state exposure for patients with impaired renal function. Results from forest plots reveal that patients with moderate to severe renal impairment or end stage renal disease are associated with significantly higher Cssmax and AUC compared to patients with normal renal function. The proposed final POP PK model could be employed in defining a TC-5214 dosage regimen in patients with impaired renal function.