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Holger Stark

Publications and source records attributed to Holger Stark.

At least 55 records · Page 3Linked to original sources
PubMed2004

Capillary condensation in liquid-crystal colloids.

We study capillary condensation between two spherical particles dispersed in the isotropic phase of a nematic liquid crystal. Within the Landau-de Gennes theory, we calculate interaction energies due to the formation of capillary bridges that reproduce experimental observations. Close to the critical point of the transition line separating the no-bridge from the bridge configuration, fluctuations in the particle cluster might be described by an effective two-state system. We show that the transition line vanishes for small particles and that the shape of the interaction potential depends on particle size.

Journal Article↗
PubMed2004

Structural variations of 1-(4-(phenoxymethyl)benzyl)piperidines as nonimidazole histamine H3 receptor antagonists.

Recent bioisoteric replacements in histamine H3 receptor ligands with an exchange of the imidazole moiety by a piperidino group as well as of the trimethylene chain in 4-((3-phenoxy)propyl)-lH-imidazole derivatives (proxifan class) by an alpha,alpha'-xylendiyl linker represents the starting point in the development of 1-(4-(phenoxymethyl)benzyl)piperidines as a new class of nonimidazole histamine H3 receptor antagonists. According to different strategies in optimization of imidazole-containing antagonists the central benzyl phenyl ether moiety was replaced by numerous other polar functionalities. Additionally, the ortho- and meta-analogues of the lead were synthesized to determine the influence of the position of the piperidinomethyl substituent. The new compounds were tested in an in vitro binding assay for their affinities for cloned human H3 receptors stably expressed in CHO-K1 cells and for their oral in vivo potencies brain in a functional screening assay in the brain of mice. Additionally, activities of selected compounds were determined in the guinea-pig ileum functional test model. In contrast to the analogues ortho-substituted compounds all other compounds maintained respectable affinities for the human H3 receptor (-log Ki values 6.3-7.5). Despite the results from other classes of compounds the 4-methyl substituted derivatives generally displayed higher affinities than the corresponding 4-chloro substituted compounds. In vivo only the inverse phenyl benzyl ether (3) showed worthwhile antagonist potencies.

Animals↗
PubMed2004

4-(omega-(alkyloxy)alkyl)-1H-imidazole derivatives as histamine H(3) receptor antagonists/agonists.

In an effort to develop new histamine H(3) receptor antagonists usable as pharmacological tools we present here novel unsymmetrical ether derivatives. Etherification of different omega-(1H-imidazol-4-yl)alkyl scaffolds led to compounds containing alkyl chains of increasing lengths either with or without unsaturated termini, cycloalkyl or arylalkyl moieties, or additional heteroatoms. When investigated in an in vitro assay on rat synaptosomes, the majority of compounds displayed potencies in the low nanomolar concentration range at the H(3) receptor, e.g., 4-(3-(3-cyclopentylpropyloxy)propyl)-1H-imidazole (27, K(i) = 7 nM). FUB 465, 4-(3-(ethoxy)propyl)-1H-imidazole (14), a useful tool for the characterization of constitutive activity of H(3) receptors in vivo in rodents, proved to be of high oral in vivo potency in mice (ED(50) = 0.26 mg/kg). Further, the influence of chosen compounds on specific [(35)S]GTPgammaS binding was assayed on HEK293 cell membranes expressing the human histamine H(3) receptor revealing partial agonism of the compounds in this particular model. These distinct responses are further hints for "protean agonism" in this class of compounds. Additionally, selected compounds were functionally investigated in vitro on isolated organs of the guinea-pig at H(3), H(1), and H(2) receptors.

Animals↗
PubMed2004

Interaction between two spherical particles in a nematic liquid crystal.

We numerically investigate the interaction between two spherical particles in a nematic liquid crystal mediated by elastic distortions in the orientational order. We pay attention to the cases where two particles with equal radii R0 impose rigid normal anchoring on their surfaces and carry a pointlike topological defect referred to as a hyperbolic hedgehog. To describe the geometry of our system, we use bispherical coordinates, which prove useful in the implementation of boundary conditions at the particle surfaces and at infinity. We adopt the Landau-de Gennes continuum theory in terms of a second-rank tensor order parameter Q(ij) for the description of the orientational order of a nematic liquid crystal. We also utilize an adaptive mesh refinement scheme that has proven to be an efficient way of dealing with topological defects whose core size is much smaller than the particle size. When the two "dipoles," composed of a particle and a hyperbolic hedgehog, are in parallel directions, the two-particle interaction potential is attractive for large interparticle distances D and proportional to D-3 as expected from the form of the dipole-dipole interaction, until the well-defined potential minimum at D approximately 2.46 R0 is reached. For the antiparallel configuration with no hedgehogs between the two particles, the interaction potential is repulsive and behaves as D-2 for D less than or approximately equal 10R0, which is stronger than the dipole-dipole repulsion (approximately D-3 ) expected theoretically as an asymptotic behavior for large D.

Journal Article↗
PubMed2004

Three-dimensional structure of a pre-catalytic human spliceosomal complex B.

Major structural changes occur in the spliceosome during its transition from the fully assembled complex B to the catalytically activated spliceosome. To understand the rearrangement, it is necessary to know the detailed three-dimensional structures of these complexes. Here, we have immunoaffinity-purified human spliceosomes (designated B Delta U1) at a stage after U4/U6.U5 tri-snRNP integration but before activation, and have determined the three-dimensional structure of B Delta U1 by single-particle electron cryomicroscopy at a resolution of approximately 40 A. The overall size of the complex is about 370 x 270 x 170 A. The three-dimensional structure features a roughly triangular body linked to a head domain in variable orientations. The body is very similar in size and shape to the isolated U4/U6.U5 tri-snRNP. This provides initial insight into the structural organization of complex B.

Catalysis↗
PubMed2004

Development of novel 1,2,3,4-tetrahydroisoquinoline derivatives and closely related compounds as potent and selective dopamine D3 receptor ligands.

Based on N-alkylated 1,2,3,4-tetrahydroisoquinoline derivatives, which are structurally related to the partial agonist BP 897, a series of novel, selective dopamine D3 receptor antagonists has been synthesised. Derivatisation included changes in the arylamide moiety and the tetrahydroisoquinoline substructure leading to compounds with markedly improved selectivities and affinities in the low nanomolar concentration range. From the 55 structures presented here, (E)-3-(4-iodophenyl)-N-(4-(1,2,3,4-tetrahydroisoquinolin-2-yl)butyl)acrylamide (51) has high affinity (Ki(hD3)=12 nM) and a 123-fold preference for the D3 receptor relative to the D2 receptor subtype. Its pharmacological profile offers the prospect of a novel radioligand as a tool for various dopamine D3-receptor-related in vitro and in vivo investigations.

Animals↗
PubMed2004

Hydrodynamic coupling of two rotating spheres trapped in harmonic potentials.

We theoretically study in detail the hydrodynamic coupling of two equal-sized colloidal spheres at low Reynolds numbers assuming the particles to be harmonically trapped with respect to both their positions and orientations. By taking into account the rotational motion, we obtain a rich spectrum of collective eigenmodes whose properties we determine on the basis of pure symmetry arguments. Extending recent investigations on translational correlations [J.-C. Meiners and S. R. Quake, Phys. Rev. Lett. 82, 2211 (1999)], we derive the complete set of autocorrelation and cross-correlation functions emphasizing the coupling of rotation to translation which we illustrate in a few examples. An important feature of our system is the self-coupling of translation and rotation of one particle mediated by the neighboring particle that is clearly visible in the appropriate autocorrelation function. This coupling is a higher-order effect and therefore not included in the widely used Rotne-Prager approximation for the hydrodynamic mobilities.

Journal Article↗
PubMed2004

Wetting of a spherical particle by a nematic liquid crystal.

We discuss how the curvature of a substrate influences wetting by a nematic liquid crystal concentrating on the surface of a spherical particle. Our investigation is based on Landau-de Gennes free energy formulated in terms of second-rank nematic order parameter Q(ij). We review the method to treat wetting transitions in curved geometries and calculate the wetting phase diagram in terms of the temperature and a surface coupling parameter. We find that the length of the prewetting line which corresponds to the boundary-layer transitions introduced by Sheng [Phys. Rev. A 26, 1610 (1982)] gradually decreases with a decrease in particle radius until it vanishes completely below a critical radius of about 100 nm. The prewetting line ends at a critical point which we study in detail. By interpreting the effect of curvature as an effective shift in temperature in Landau-de Gennes theory, we are able to formulate a good estimate for the critical temperature as a function of the inverse particle radius. It demonstrates that splay deformations around the particle significantly influence nematic wetting of curved surfaces.

Journal Article↗
PubMed2004

Search for histamine H(3) receptor ligands with combined inhibitory potency at histamine N-methyltransferase: omega-piperidinoalkanamine derivatives.

In an effort to design new hybrid compounds with dual properties, i.e. binding affinity at histamine H(3) receptors and inhibitory potency at the catabolic enzyme histamine N(tau)-methyltransferase (HMT), a novel series of 1-substituted piperidine derivatives was synthesized. This alicyclic heterocycle is structurally linked via aminoalkyl spacers of variable lengths to additional aromatic carbo- or hetero-cycles. These new hybrid drugs were pharmacologically evaluated regarding their binding affinities at recombinant human H(3) receptors, stably expressed in CHO cells, and in a functional assay for their inhibitory potencies at rat kidney HMT. All compounds investigated proved to be H(3) receptor ligands with binding affinities in the micro- to nanomolar concentration range despite significant differences in the type of the aromatic moiety introduced. The most potent compound in this series was the quinoline derivative 20 (K(i) = 5.6 nM). Likewise, all new ligands studied showed impressive HMT inhibitory activities. Here, compounds 5, 10, 14 and 18-20 exhibited submicromolar potencies (IC(50) = 0.061-0.56 microM). The aminomethylated quinoline 19 showed almost the same, well balanced nanomolar activities on both targets. In this study, new hybrid compounds with a dual mode biological action were developed. These pharmacological agents are valuable leads for further development and candidates for treatment of histamine-dependent disorders.

Alkanes↗
PubMed2004

Medicinal chemical and pharmacological aspects of imidazole-containing histamine H3 receptor antagonists.

The first antagonists known for the histamine H3 receptor were mono-substituted imidazole-containing compounds like thioperamide. Meanwhile numerous novel leads have been developed possessing improved affinities, selectivities, specificities, and pharmacokinetic properties. Scope and limitations of this promising class are discussed concerning their structure-activity relationships as well as pharmacological and potential therapeutic aspects.

Animals↗
PubMed2003

Persistent random walk in a honeycomb structure: light transport in foams.

We study light transport in a honeycomb structure as the simplest two-dimensional model foam. We apply geometrical optics to set up a persistent random walk for the photons. For three special injection angles of 30 degrees, 60 degrees, and 90 degrees relative to a hexagon's edge, we are able to demonstrate by analytical means the diffusive behavior of the photons and to derive their diffusion constants in terms of intensity reflectance, edge length, and velocity of light. Numerical simulations reveal an interesting dependence of the diffusion constant on the injection angle in contrast to the usual assumption that in the diffusive limit the photon has no memory for its initial conditions. Furthermore, for injection angles close to 30 degrees, the diffusion constant does not converge to the value at 30 degrees. We explain this observation in terms of a two-state model.

Journal Article↗
PubMed2003

Protean agonism at histamine H3 receptors in vitro and in vivo.

G protein-coupled receptors (GPCRs) are allosteric proteins that adopt inactive (R) and active (R*) conformations in equilibrium. R* is promoted by agonists or occurs spontaneously, leading to constitutive activity of the receptor. Conversely, inverse agonists promote R and decrease constitutive activity. The existence of another pharmacological entity, referred to as "protean" agonists (after Proteus, the Greek god who could change shape), was assumed on theoretical grounds. It was predicted from the existence of constitutive activity that a same ligand of this class could act either as an agonist or an inverse agonist at the same GPCR. Here, we show that proxyfan, a high-affinity histamine H3-receptor ligand, acts as a protean agonist at recombinant H3 receptors expressed in the same Chinese hamster ovary cells. In support of the physiological relevance of the process, we show that proxyfan also behaves as a protean agonist at native H3 receptors known to display constitutive activity. On neurochemical and behavioral responses in rodents and cats, proxyfan displays a spectrum of activity ranging from full agonism to full inverse agonism. Thus, protean agonism demonstrates the existence of ligand-directed active states LR* different from, and competing with, constitutively active states R* of GPCRs, and defines a pharmacological entity with important therapeutic implications.

Animals↗
PubMed2003

N-(omega-(4-(2-methoxyphenyl)piperazin-1-yl)alkyl)carboxamides as dopamine D2 and D3 receptor ligands.

The dopamine D(3) receptor is recognized as a potential therapeutic target for the treatment of various neurological and psychiatric disorders. Targetting high affinity and D(3) versus D(2) receptor-preferring ligands, the partial agonist BP 897 was taken as a lead structure. Variations in the spacer and the aryl moiety led to N-alkylated 1-(2-methyoxyphenyl)piperazines with markedly improved affinity and selectivity. Molecular modeling studies supported the structural development. Pharmacophore models for dopamine D(2) and D(3) receptor ligands were developed from their potentially bioactive conformation and were compared in order to get insight into molecular properties of importance for D(2)/D(3) receptor selectivity. For the 72 compounds presented here, an extended and more linear conformation in the aliphatic or aryl spacers turned out to be crucial for dopamine D(3) receptor selectivity. Structural diversity in the aryl moiety (benzamides, heteroarylamides, arylimides) had a major influence on (sub)nanomolar D(3) receptor affinity, which was optimized with more rigid aryl acrylamide derivatives. Compound 38 (ST 280, (E)-4-iodo-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)cinnamoylamide) displayed a most promising pharmacological profile (K(i) (hD(3)) = 0.5 nM; K(i) (hD(2L)) = 76.4 nM; selectivity ratio of 153), and above that, compound 38 offered the prospect of a novel radioligand as a pharmacological tool for various D(3) receptor-related in vitro and in vivo investigation.

Animals↗
PubMed2003

Imidazole derivatives as a novel class of hybrid compounds with inhibitory histamine N-methyltransferase potencies and histamine hH3 receptor affinities.

In this study, a novel series of imidazole-containing compounds with dual properties, that is, inhibitory potency at the enzyme histamine N(tau)-methyltransferase (HMT) and antagonist potency at histamine H(3) receptors was designed and synthesized. Pharmacologically, these new hybrid drugs were evaluated in functional assays for their inhibitory potencies at rat kidney HMT and for their antagonist activities on synaptosomes of rat cerebral cortex. For selected compounds, binding affinities at recombinant human histamine H(3) receptors were determined. The first compounds (1-10) of the series proved to be H(3) receptor ligands of high potency at rat synaptosomes or of high binding affinity at human H(3) receptors, respectively, but of only moderate activity as inhibitors of rat kidney HMT. In contrast, aminoquinoline- or tetrahydroacridine-containing derivatives 11-17 also displayed HMT inhibitory potency in the nanomolar concentration range. Preliminary data from molecular modeling investigations showed that the imidazole derivative 15 and the HMT inhibitor quinacrine possess identical binding areas. The most interesting compound (14) is simultaneously a highly potent H(3) receptor ligand (K(i)=4.1nM) and a highly potent HMT inhibitor (IC(50)=24nM), which makes this derivative a valuable pharmacological tool for further development.

Aminoquinolines↗
PubMed2003

Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function.

In monkeys rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), expression of the dopamine D3 receptor was decreased. However, levodopa-induced dyskinesia (LID), similar to the debilitating and pharmacoresistant involuntary movements elicited after long-term treatment with levodopa in patients with Parkinson disease (PD), was associated with overexpression of this receptor. Administration of a D3 receptor-selective partial agonist strongly attenuated levodopa-induced dyskinesia, but left unaffected the therapeutic effect of levodopa. In contrast, attenuation of dyskinesia by D3 receptor antagonists was accompanied by the reappearance of PD-like symptoms. These results indicated that the D3 receptor participated in both dyskinesia and the therapeutic action of levodopa, and that partial agonists may normalize D3 receptor function and correct side effects of levodopa therapy in patients with PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗