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C Thomsen

Publications and source records attributed to C Thomsen.

At least 55 records · Page 3Linked to original sources
PubMed1999

1-(1,2,5-Thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2,6)]heptanes as new potent muscarinic M1 agonists: structure-activity relationship for 3-aryl-2-propyn-1-yloxy and 3-aryl-2-propyn-1-ylthio derivatives.

Two new series of 1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2, 6)]heptanes were synthesized and evaluated for their in vitro activity in cell lines transfected with either the human M1 or M2 receptor. 3-Phenyl-2-propyn-1-yloxy and -1-ylthio analogues substituted with halogen in the meta position showed high functional potency, efficacy, and selectivity toward the M1 receptor subtype. A quite unique functional M1 receptor selectivity was observed for compounds 8b, 8d, 8f, 9b, 9d, and 9f. Bioavailability studies in rats indicated an oral bioavailability of about 20-30%, with the N-oxide as the only detected metabolite.

Animals↗
PubMed1999

Pentylenetetrazol-induced seizures increase [3H]L-2-amino-4-phosphonobutyrate binding in discrete regions of the rat brain.

Convulsions were induced in rats by a single injection of pentylenetetrazol (PTZ) and [3H]L-2-amino-4-phosphonobutyrate ([3H]L-AP4) in vitro receptor autoradiography was used to evaluate the effects on the expression of group III metabotropic glutamate receptors. Significant increases by 60-80% in [3H]L-AP4 binding was observed in the frontal parts of cortex (sensory, motor and cingulate cortex) and by 28% in the molecular layer of the cerebellar cortex 24 h after PTZ-induced seizures. Since group III metabotropic glutamate receptors has an inhibitory effect on glutamatergic transmission, the observed increases in binding may indicate that these receptors serve as a mechanism for preventing further seizure activity.

Aminobutyrates↗
PubMed1999

Magnetic resonance imaging of valvular heart disease.

The optimum management of patients with valvular heart diseases requires accurate and reproducible assessment of the valvular lesion and its hemodynamic consequences. Magnetic resonance imaging (MRI) techniques, such as volume measurements, signal-void phenomena, and velocity mapping, can be used in an integrated approach to gain qualitative and quantitative information on valvular heart disease as well as ventricular dimensions and functions. Thus, MRI may be advantageous to the established diagnostic tools in assessing the severity of valvular heart disease as well as monitoring the lesion and predicting the optimal timing for valvular surgery. This paper reviews the validation of these MRI techniques in assessing valvular heart disease and discusses some typical pitfalls of the techniques, including suggestions for solutions.J. Magn. Reson. Imaging 1999;10:627-638.

Blood Flow Velocity↗
PubMed1999

Comparison of the effects of a monounsaturated fat diet and a high carbohydrate diet on cardiovascular risk factors in first degree relatives to type-2 diabetic subjects.

OBJECTIVE: Recent studies have demonstrated beneficial metabolic effects of dietary monounsaturated fatty acids (MUFA) in Type-2 diabetes mellitus (Type-2 DM). The question arises if dietary MUFA also has desirable effects on risk markers in subjects with high risk of developing Type-2 DM. SETTING: University department of endocrinology. SUBJECTS: Sixteen healthy, first-degree relatives (six men, 10 women, age (mean+/-s.d.): 35+/-2 years) with normal oral glucose tolerance tests. INTERVENTIONS: Randomised study with two 4-week treatment periods with either a carbohydrate-rich (CHO) diet (55 E% carbohydrate, 30 E% fat, 15 E% protein) or a diet rich in olive oil [MUFA 40 E% fat (25 E% as MUFA), 45 E% carbohydrate, 15 E% protein]. The periods were divided by a 4-week wash-out period. RESULTS: Similar lowering effects on total cholesterol, low density lipoprotein (LDL)-cholesterol, triglyceride and apoB levels were seen after the two diets. Slightly higher levels of high-density lipoprotein (HDL)-cholesterol (1.4+/-0.4 vs 1.3+/-0.4 mmol/l, P<0. 0001) and apoA-1 (1.2+/-0.3 vs 1.1+/-0.3 mmol/l, P<0.05) were found in the MUFA-diet. Furthermore, the insulin sensitivity, as assessed by Bergman's minimal model, and the first response insulin areas were similar, as were the 24-h blood pressures and the von Willebrand Factor (vWF) levels. CONCLUSIONS: Isocaloric diets rich in MUFA or rich in carbohydrate, respectively, seem to have similar effects on cardiovascular risk factors in persons at high risk of developing Type-2 DM. A potential risk, however, on body weight of high-fat diets should be kept in mind. SPONSORSHIP: This study was supported by grants from the Danish Diabetes Association, Institute of Clinical Experimental Research, Aarhus University, The Danish Heart Foundation, The Danish Medical Research Council, Velux Foundation, Poul and Erna Sehested Hansens Foundation, Mogens Svarre Mogensens Foundation.

Adult↗
PubMed1999

Contribution of metabotropic glutamate receptor mGluR4 to L-2-[3H]amino-4-phosphonobutyrate binding in mouse brain.

The binding of L-2-[3H]amino-4-phosphonobutyrate ([3H]L-AP4) was examined in brain sections of wild-type mice and mice lacking the mGluR4 subtype of metabotropic glutamate receptors (mGluRs). Very high relative densities of [3H]L-AP4 binding were observed in the molecular layer of the cerebellar cortex, the nucleus basalis, the outer layer of the superior colliculus, and the substantia nigra. In mGluR4 knock-out mice, very low levels of binding were observed in these regions. The moderate levels of binding observed with wild-type mice in the molecular layer of the hippocampal dentate gyrus and in the thalamus were absent in mGluR4 knock-out mice. In contrast, the moderate levels observed in most of the cerebral cortex, caudate putamen, and globus pallidus were not different in mGluR4 knock-out mice compared with wild-type. In these regions, mGluR8 is likely to be labeled by [3H]L-AP4 because mGluR8 is expressed in such brain regions and, like mGluR4, has high affinity for L-AP4. We conclude that mGluR4 contributes substantially to the high-affinity binding site for [3H]L-AP4 in several regions of mouse brain, including cerebellar cortex, nucleus basalis, thalamus, superior colliculus, substantia nigra, and hippocampal dentate gyrus.

Aminobutyrates↗
PubMed1999

Astroglia contain a specific transport mechanism for N-acetyl-L-aspartate.

N-Acetylaspartate (NAA) is the second most abundant amino acid in the adult brain. It is located and synthesized in neurons and probably degraded in the glia compartment, but the transport mechanisms are unknown. Rat primary neuron and astrocyte cell cultures were exposed to the L isomer of [3H]NAA and demonstrated concentration-dependent uptake of [3H]NAA with a Km approximately 80 microM. However, Vmax was 23+/-6.4 pmol/mg of protein/min in astrocytes but only 1.13+/-0.4 pmol/mg of protein/min in neurons. The fact that neuron cultures contain 3-5% astrocytes suggests that the uptake mechanism is expressed only in glial cells. The astrocyte uptake was temperature and sodium chloride dependent and specific for L-NAA. The affinity for structural analogues was (IC50 in mM) as follows: L-NAA (0.12) > N-acetylaspartylglutamate (0.4) > N-acetylglutamate (0.42) > L-aspartate (>1) > L-glutamate (>1) > or = DL-threo-beta-hydroxyaspartate > N-acetyl-L-histidine. The naturally occurring amino acids showed no inhibitory effect at 1 mM. The glutamate transport blocker trans-pyrrolidine-2,4-dicarboxylate exhibited an IC50 of 0.57 mM, whereas another specific glutamate transport inhibitor, DL-threo-beta-hydroxyaspartate, had an IC50 of >1 mM. The experiments suggest that NAA transport in brain parenchyma occurs by a novel type of sodium-dependent carrier that is present only in glial cells.

Animals↗
PubMed1999

Differential effects of saturated and monounsaturated fatty acids on postprandial lipemia and incretin responses in healthy subjects.

BACKGROUND: Elevations of postprandial triacylglycerol-rich plasma lipoproteins and suppressions of HDL-cholesterol concentrations are considered potentially atherogenic. Long-term studies have shown beneficial effects of monounsaturated fatty acids (eg, oleic acid) on fasting lipid and lipoprotein concentrations in humans. A direct stimulatory effect of oleic acid on the secretion of glucagon-like peptide 1 (GLP-1) was shown in animal studies. OBJECTIVE: We compared the postprandial responses of glucose, insulin, fatty acids, triacylglycerol, gastric inhibitory polypeptide (GIP), and GLP-1 to test meals rich in saturated and monounsaturated fatty acids. DESIGN: Ten young, lean, healthy persons ingested 3 meals: an energy-free soup consumed with 50 g carbohydrate (control meal), the control meal plus 100 g butter, and the control meal plus 80 g olive oil. Triacylglycerol and retinyl palmitate responses were measured in total plasma, in a chylomicron-rich fraction, and in a chylomicron-poor fraction. RESULTS: No significant differences in glucose, insulin, or fatty acid responses to the 2 fat-rich meals were seen. Plasma triacylglycerol responses were highest after the butter meal, with chylomicron triacylglycerol rising 2.5-5-fold. Retinyl palmitate responses were higher and more prolonged after the butter meal than after the control and olive oil meals, whereas both postprandial HDL-cholesterol concentrations and GLP-1 and GIP responses were higher after the olive oil meal than after the butter meal. CONCLUSIONS: Olive oil induced lower triacylglycerol concentrations and higher HDL-cholesterol concentrations than butter, without eliciting differences in concentrations of glucose, insulin, or fatty acids. Furthermore, olive oil induced higher concentrations of GLP-1 and GIP than did butter, which may point to a relation between fatty acid composition, incretin responses, and triacylglycerol metabolism in the postprandial phase.

Adult↗
PubMed1999

Increased insulin secretion and normalization of glucose tolerance by cholinergic agonism in high fat-fed mice.

Increased insulinotropic activity by the cholinergic agonist carbachol exists in insulin-resistant high fat-fed C57BL/6J mice. We examined the efficiency and potency of carbachol to potentiate glucose-stimulated insulin secretion and to improve glucose tolerance in these animals. Intravenous administration of carbachol (at 15 and 50 nmol/kg) markedly potentiated glucose (1 g/kg)-stimulated insulin secretion in mice fed both a control and a high-fat diet (for 12 wk), with a higher relative potentiation in high fat-fed mice measured as increased (1-5 min) acute insulin response and area under the 50-min insulin curve. Concomitantly, glucose tolerance was improved by carbachol. In fact, carbachol normalized glucose-stimulated insulin secretion and glucose tolerance in mice subjected to a high-fat diet. Carbachol (>100 nmol/l) also potentiated glucose-stimulated insulin secretion from isolated islets with higher efficiency in high fat-fed mice. In contrast, binding of the muscarinic receptor antagonist [N-methyl-(3)H]scopolamine to islet muscarinic receptors and the contractile action of carbachol on ileum muscle strips were not different between the two groups. We conclude that carbachol normalizes glucose tolerance in insulin resistance.

Animals↗
PubMed1999

Triggering in quantitative diffusion imaging with single-shot EPI.

PURPOSE: The aim of this study was to evaluate any possible effects of brain motion, CSF pulsations and other possible sources of physiological motion in electrocardiographic (ECG) triggered and non-triggered single-shot echo-planar imaging (EPI) measurements of diffusion. MATERIAL AND METHODS: Three different triggering protocols were evaluated in 6 healthy volunteers: 1) ECG triggering with time delay (TD) 100 ms; 2) ECG triggering with TD 400 ms; and 3) no triggering at all. RESULTS: The results obtained showed that white matter mean apparent diffusion coefficient (ADC) values were similar for all triggering protocols and that the reproducibility in ADC measurements using diffusion-weighted (DW) EPI was good. The average standard deviation of the ADC values was, however, higher for ADC maps obtained without ECG triggering. CONCLUSION: The use of prospective diastolic ECG triggering significantly improves the accuracy of quantitative diffusion measurements but for routine clinical diffusion imaging, where quantitative data is of less importance, the accuracy obtained without ECG triggering can be considered adequate.

Adult↗
PubMed1999

CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding.

Metabotropic glutamate receptors (mGluRs) are a family of G protein-coupled receptors characterized by a large, extracellular N-terminal domain comprising the glutamate-binding site. In the current study, we examined the pharmacological profile and site of action of the non-amino-acid antagonist 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt). CPCCOEt selectively inhibited glutamate-induced increases in intracellular calcium at human mGluR1b (hmGluR1b) with an apparent IC50 of 6.5 microM while having no agonist or antagonist activity at hmGluR2, -4a, -5a, -7b, and -8a up to 100 microM. Schild analysis indicated that CPCCOEt acts in a noncompetitive manner by decreasing the efficacy of glutamate-stimulated phosphoinositide hydrolysis without affecting the EC50 value or Hill coefficient of glutamate. Similarly, CPCCOEt did not displace [3H]glutamate binding to membranes prepared from mGluR1a-expressing cells. To elucidate the site of action, we systematically exchanged segments and single amino acids between hmGluR1b and the related subtype, hmGluR5a. Substitution of Thr815 and Ala818, located at the extracellular surface of transmembrane segment VII, with the homologous amino acids of hmGluR5a eliminated CPCCOEt inhibition of hmGluR1b. In contrast, introduction of Thr815 and Ala818 at the homologous positions of hmGluR5a conferred complete inhibition by CPCCOEt (IC50 = 6.6 microM), i.e., a gain of function. These data suggest that CPCCOEt represents a novel class of G protein-coupled receptor antagonists inhibiting receptor signaling without affecting ligand binding. We propose that the interaction of CPCCOEt with Thr815 and Ala818 of mGluR1 disrupts receptor activation by inhibiting an intramolecular interaction between the agonist-bound extracellular domain and the transmembrane domain.

Alanine↗
PubMed1998

Muscarinic agonists exhibit functional dopamine antagonism in unilaterally 6-OHDA lesioned rats.

(5R,6R) 6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]oc tane (PTAC) is a selective muscarinic ligand with high affinity for central muscarinic receptors, agonist mode of action at the muscarinic M2 and M4 receptor subtypes and substantially less or no affinity for central dopamine receptors. In the present study PTAC, as well as the muscarinic agonists oxotremorine, RS86 and pilocarpine, inhibited dopamine D1 and D2 receptor agonist induced contralateral rotation in unilaterally 6-OHDA lesioned rats. The dose of SKF 38393 used to induce contralateral rotation also caused an intense Fos protein immunoreactivity in the rat dorsolateral striatum on the lesioned site which was inhibited by PTAC indicating that the inhibition of rotation by PTAC was not due to non-specific peripheral side effects.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1998

Muscarinic agonists with antipsychotic-like activity: structure-activity relationships of 1,2,5-thiadiazole analogues with functional dopamine antagonist activity.

Muscarinic agonists were tested in two models indicative of clinical antipsychotic activity: conditioned avoidance responding (CAR) in rats and inhibition of apomorphine-induced climbing in mice. The standard muscarinic agonists oxotremorine and pilocarpine were both active in these tests but showed little separation between efficacy and cholinergic side effects. Structure-activity relationships of the alkylthio-1,2,5-thiadiazole azacyclic type muscarinic partial agonists are shown, revealing the exo-6-(3-propyl/butylthio-1,2, 5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane analogues (4a,b and 9a, b) to be the most potent antipsychotic agents with large separation between efficacy and cholinergic side effects. The lack of enantiomeric selectivity suggests the pharmacophoric elements are in the mirror plane of the compounds. A model explaining the potency differences of closely related compounds is offered. The data suggest that muscarinic agonists act as functional dopamine antagonists and that they could become a novel treatment of psychotic patients.

Animals↗
PubMed1998

Identification of side chains on 1,2,5-thiadiazole-azacycles optimal for muscarinic m1 receptor activation.

Series of analogs to the functional m1 selective agonist, xanomeline (hexyloxy-TZTP), were evaluated for their in vitro m1 efficacy in cell lines transfected with the human m1 receptor. Systematic variation of the side chain and the azacyclic ring led to the discovery of potent muscarinic agonists with robust m1 efficacy, all having the phenylpropargyloxy/thio as the side chain. The most selective compound was the phenylpropargylthio-[3.2.1] endo analog 28, which is a potent and efficacious m1 agonist with no m2 activity.

Animals↗
PubMed1998

The synthesis of new adenosine A3 selective ligands containing bioisosteric isoxazoles.

The synthesis and purinergic receptor binding of novel adenosine A3 ligands is described. Many selective A3 receptor agonists e.g. N-(3-iodobenzyl)adenosine-5'-methyluronamide (IB-MECA) contain a 4'-ribosylalkylamide moiety. We found that this amide and other 4'-functional groups could be replaced with an isosteric isoxazole, and the target molecules retained potent binding to the recombinant human A3 receptor.

Adenosine↗
PubMed1998

Effects of the M1 agonist xanomeline on processing of human beta-amyloid precursor protein (FAD, Swedish mutant) transfected into Chinese hamster ovary-m1 cells.

Complementary DNA (cDNA) encoding human beta-amyloid precursor protein familial Alzheimer's disease (FAD) Swedish mutant (beta APPSM) form was cloned into a mammalian expression vector (PK255) containing the CMV promoter. The vector was transfected into Chinese hamster ovary cells containing human muscarinic m1 receptors (CHO-m1), and clonal cells stably expressing beta APPSM were isolated. The effects of m1-receptor activation by the selective m1 agonist xanomeline and the non-selective muscarinic agonist carbachol on processing of beta APPSM to release soluble APP (APPs) and beta-amyloid peptide (A beta) were compared. Xanomeline stimulated APP release with a potency 1000-fold greater than that observed for carbachol. Concentrations of carbachol and xanomeline producing maximal effects on APPs release reduced the secretion of A beta by 28 and 46%, respectively. These results extend previous studies with xanomeline and suggest that cholinergic replacement therapy for Alzheimer's disease may reduce amyloid deposition.

Alzheimer Disease↗
PubMed1998

Roles of metabotropic glutamate receptor subtypes in modulation of pentylenetetrazole-induced seizure activity in mice.

The anticonvulsant or proconvulsant properties of ligands at metabotropic glutamate receptors (mGluRs) were examined in a chemoconvulsant model using pentylenetetrazole (PTZ). Mice received mGluR ligands by intracerebroventricular (i.c.v.) infusion prior to a subcutaneous injection of PTZ and the latency to onset of tonic convulsions was recorded. The group I mGluR antagonist 1-aminoindan-1,5-dicarboxylic acid (AIDA) dose-dependently antagonised PTZ-induced seizures with a mean ED50 value of 465 nmol. In contrast, the selective group I mGluR agonist, (S)-3,5-dihydroxyphenylglycine [(S)-DHPG], was proconvulsive and decreased the PTZ-induced seizure latency (ED50=60 nmol i.c.v.). A selective agonist of group II mGluRs, (1S,3S)-1-aminocyclopentane dicarboxylic acid [(1S,3S)-ACPD], was proconvulsive but did not affect PTZ-induced seizure latency. Moreover, the proconvulsant effect of (IS,3S)-ACPD was not blocked by the mGluR2 antagonist, alpha-methylserine-O-phosphate monophenyl ester but was blocked by AIDA suggesting the involvement of group I mGluRs. (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCG-IV), which is a potent mGluR2 antagonist and a group III mGluR agonist at higher doses, increased the PTZ-induced seizure latency (ED50=51 nmol) and this effect was fully reversed by the group III mGluR antagonist, (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4). Similarly, the group III mGluR agonist 1-amino-3-(phosphonomethylene)cyclobutanecarboxylate (cyclobutylene-AP5) increased the PTZ-induced seizure latency (ED50=12 nmol) in a MAP4-sensitive manner. Collectively, these data suggest that mGluR ligands modulate PTZ-induced seizure activity in mice by either antagonizing group I mGluRs or activating group III mGluRs.

Animals↗
PubMed1998

Quantitative diffusion coefficient maps using fast spin-echo MRI.

In this work, we have evaluated the performance of a diffusion-sensitive fast spin-echo (FSE) pulse sequence. The proposed pulse sequence utilises velocity-compensating diffusion-encoding gradients and includes the collection of navigator echoes. Spoiler gradients were inserted in the slice-selecting direction to minimise effects from stimulated echoes. Calculations of the b values showed that cross-terms between imaging gradients and diffusion gradients only led to a marginal increase of b values. Pixel-wise calculation of apparent diffusion coefficient (ADC) maps was performed numerically, considering cross-terms between diffusion-encoding and imaging gradients. The sequences investigated used echo train lengths of 16, 8 and 4 echoes and were encoded in either the slice-, frequency- or phase-encoding direction. In order to allow for higher b values a pulse-sequence version using non-motion compensating diffusion-encoding gradients was written. Phantom measurements were performed and the diffusion coefficients of water and acetone were reasonable. Seven healthy volunteers (age 28-50 years) were examined and apparent diffusion coefficient values agreed well with expected values. Diffusion-weighted images, apparent diffusion coefficient maps and images corresponding to the trace of the diffusion tensor of good quality were retrieved in vivo.

Adult↗