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H Hübner

Publications and source records attributed to H Hübner.

At least 19 recordsLinked to original sources
PubMed2006

Tissue distribution of radioiodinated FAUC113: assessment of a pyrazolo(1,5-a) pyridine based dopamine D4 receptor radioligand candidate.

AIM: Disturbances of the D4 receptor subtype have been implicated in the genesis of a broad range of psychiatric disorders. In order to assess the suitability of a radioiodinated analogue of the D4-selective ligand FAUC 113 for tracer studies in vivo, we investigated the in-vivo stability, biodistribution and brain-uptake of 7-(131)I-FAUC 113 in Sprague-Dawley rats. METHODS: Radiolabelling was carried out with high radiochemical yield and specific activity. After intravenous injection, blood and tissue samples, taken at designated time intervals, were collected for analysis. Analyses of metabolites were performed by radio-hplc and radio-tlc. For in-vivo evaluation, sagittal cryo-sections of the rat brain were investigated by in-vitro and ex-vivo autoradiography on a mu-Imager system. RESULTS: 7-(131)I-FAUC 113 was rapidly cleared from blood. Highest uptake was observed in kidney (0.603 +/- 0.047% ID/g, n = 4) and liver (0.357 +/- 0.070% ID/g, n = 4) at 10 min p.i.; 7-(131)I-FAUC 113 displayed rapid uptake (0.21-0.26% ID/g) and fast clearance in various brain regions consistent with the determined logP-value of 2.36 +/- 0.15 (n = 4). In-vivo stability of 7-(131)I-FAUC 113 was confirmed in the frontal cortex (>95%). Ex-vivo autoradiography revealed a frontal cortex-to-cerebellum ratio of 1.57 +/- 0.13 at 10 min p.i. (n = 6). Coinjection with L-750667 could not suppress any putative specific binding of 7-(131)I-FAUC 113. In-vitro autoradiography using authentic 7-iodo-FAUC 113 or L-750667 failed to cause significant displacement of the radioligand. CONCLUSIONS: Radioiodinated FAUC 113 does not allow imaging of D4 receptors in the rat brain in vivo nor in vitro. Further work should aim at the development of selective dopamine D4 radioligands with improved tracer characteristics, such as receptor affinity and subtype selectivity, specific activity or blood-brain barrier permeability.

Animals↗
PubMed2001

Dopaminergic 7-aminotetrahydroindolizines: ex-chiral pool synthesis and preferential D3 receptor binding.

Starting from both isomers of enantiopure asparagine, heterocyclic bioisosteres of the preferential dopamine D3 receptor agonist (R)-7-OH-DPAT were investigated when SAR studies led to the 3-formyl substituted aminoindolizine (S)-1e (FAUC 54) displaying a K(i) value of 6.0 nM for the high affinity D3 binding site. In contrast, D3 affinity of the enantiomer (R)-1e was 300 fold lower.

Animals↗
PubMed2001

Benzamide bioisosteres incorporating dihydroheteroazole substructures: EPC synthesis and SAR leading to a selective dopamine D4 receptor partial agonist (FAUC 179).

Conformationally restricted benzamide bioisosteres were investigated when the chiral phenyldihydroimidazole derivative 4e (FAUC 179) showed strong and highly selective dopamine D4 receptor binding (K(i)high=0.95nM). Mitogenesis experiments indicated partial agonist properties (42%). EPC syntheses of the target compounds of type 4 were performed starting from alpha-amino acids.

Animals↗
PubMed2001

Rationally based efficacy tuning of selective dopamine d4 receptor ligands leading to the complete antagonist 2-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213).

Structure dependent efficacy studies in the field of selective D4 ligands led to the 2-aminomethyl substituted azaindole 2 (FAUC 213) that displayed strong D4 binding, high subtype selectivity, and complete antagonist properties in ligand-induced mitogenesis experiments. According to our schematic molecular model, the intrinsic activity of the regioisomers investigated is controlled by the ability of the heterocyclic unit to interact with both elements of the D4 binding-site crevice, the aromatic microdomain in TM6, and a serine residue in TM5.

Animals↗
PubMed2001

Minor constituents of Spigelia anthelmia and their cardiac activities.

A more detailed phytochemical analysis of extracts of the aerial parts of Spigelia anthelmia L. (Loganiaceae) yielded 20 structurally related new compounds besides spiganthine and ryanodine. Structure elucidation was achieved mainly by spectroscopic methods. The compounds were tested on their cardiac and on their insect antifeedant activities.

Animals↗
PubMed2001

[Transplantation of autologous oral mucosa in the treatment of a symblepharon in Wegener's disease--a case report].

BACKGROUND: Wegener's disease, an immune vasculitis, is characterized by granulomata and vasculitis of small and large vessels. Ocular manifestations are observed in approximately half of all cases. PATIENT: We report on a 58-year-old male with severe generalized Wegener's disease which was first diagnosed in 1986. The involvement of the central nervous system became clinically manifest by a stroke, of the kidneys by incipient renal insufficiency, and of the larynx by recurrent subglottic stenosis of the trachea. The first ocular involvement, a conjunctivitis, was observed in 1988. Despite systemic immuno-suppressive therapy, local conservative therapy and repeated surgical procedures, his vision decreased bilaterally from 60/60 to hand movement (OD) and light perception only (OS) during the following years because of a massive bilateral symblepharon. Transplantation of autologous oral mucosa to the conjunctiva led to a persistent increase of vision and a good cosmetic result. CONCLUSIONS: We conclude that in patients with Wegener's disease, who have developed a symblepharon despite intensive therapy, the transplantation of oral mucosa can produce a sufficient functional and cosmetic result.

Conjunctival Diseases↗
PubMed2000

Cyanoindole derivatives as highly selective dopamine D(4) receptor partial agonists: solid-phase synthesis, binding assays, and functional experiments.

Traceless linking of diethoxymethyl (DEM)-protected 5- and 6-cyanoindoles and subsequent incorporation of phenylpiperazine derivatives led to the 2- and 3-piperazinylmethyl-substituted cyanoindoles 3a-m. Dopamine receptor binding studies on the final products 3a-m clearly indicated strong and selective recognition of the D(4) subtype which is known as a promising target for the treatment of neuropsychiatric disorders. The most interesting binding properties were observed for the 2-aminomethyl-5-cyanoindoles FAUC 299 (3f) and FAUC 316 (3j) (K(i) = 0.52 and 1.0 nM, respectively) when the fluoro derivative 3j proved extraordinary selectivity over D(1), D(2long), D(2short), and D(3) (>8600). To determine ligand efficacy, mitogenesis experiments were performed indicating partial agonist effects for the test compounds 3f,j (35% and 30%, when compared to the full agonist quinpirole).

Animals↗
PubMed2000

Conjugated enynes as nonaromatic catechol bioisosteres: synthesis, binding experiments, and computational studies of novel dopamine receptor agonists recognizing preferentially the D(3) subtype.

To evaluate nonaromatic catechol bioisosteres, the conformationally restrained enynes 1 and enediynes 2 were synthesized via palladium-catalyzed coupling as the key reaction step. Subsequent receptor binding studies at the dopamine receptor subtypes D(1), D(2 long), D(2 short), D(3), and D(4) showed highly interesting binding profiles for the enynes 1a and 1b when compared to dopamine. At the guanine nucleotide-sensitive high-affinity binding site of the D(3) receptor, the target compound 1b (K(i) = 5.2 nM) was 10-fold more potent than dopamine but less potent at the D(2) and D(4) subtypes. In contrast to dopamine the agonists 1a and 1b showed strong selectivity for the receptors of the D(2) family (D(2)-D(4)). As far as we know, this study represents the first report on nonaromatic dopamine agonists. Comparison of molecular electrostatic potentials, derived from semiempirical molecular orbital calculations, and lipophilicity maps was performed.

Alkynes↗
PubMed2000

Azepino- and diazepinoindoles: synthesis and dopamine receptor binding profiles.

Starting from the readily available building blocks 7, 10, 11, and 15, the synthesis of the fused indoles 1, 2, 5, and 6, respectively, is reported. The syntheses involved Pictet-Spengler cyclizations, Michael addition reactions, lactamization, directed metallation, and reductive amination as the key reaction steps. Radioligand displacement studies comprising the dopamine receptor subtypes D1, D2long D2short, D3, and D4.4 were performed when the diazepinoindole 6 revealed D1 and D4 affinities (Ki = 0.11 microM and 1.7 microM, respectively) which are comparable to the partial D1 agonist SKF 38393 (3b). In contrast to the benzazepine 3b, the indole based test compounds turned out less selective over the D2 and D3 receptor subtype.

Animals↗
PubMed1999

Piperidinylpyrroles: design, synthesis and binding properties of novel and selective dopamine D4 receptor ligands.

Piperidinylpyrroles of type 3 were synthesized through a modified Paal-Knorr reaction. For the introduction of pyrrole-substituents high yielding transformations including Sonogashira cross-coupling reactions were utilized. Employment of the reagent TosMIC gave access to the regioisomeric oxazolyl derivatives 7 and 11 which showed the highest dopamine D4 receptor binding of the series investigated.

Animals↗
PubMed1999

Enantio- and diastereocontrolled dopamine D1, D2, D3 and D4 receptor binding of N-(3-pyrrolidinylmethyl)benzamides synthesized from aspartic acid.

Subreceptor selectivity tuning of N-(3-pyrrolidinyl)benzamides leading to the selective dopamine D3 ligand ent1h and the derivatives 1g and 1e/ent1e which preferably recognize human D2 or D4 receptors, respectively, is described. Binding profiles were controlled by both, absolute and relative configuration. The enantiopure target compounds were synthesized from aspartic acid.

Animals↗
PubMed1999

Azaindole derivatives with high affinity for the dopamine D4 receptor: synthesis, ligand binding studies and comparison of molecular electrostatic potential maps.

Piperazinylmethyl substituted pyrazolo[1,5-a]pyridines and related heterocycles were synthesized and found to recognize selectively the dopamine D4 receptor. For the most potent derivative 10d a Ki value of 2.0 nM was observed. SAR studies including the comparison of molecular isopotential surfaces were performed.

Dopamine Antagonists↗
PubMed1999

Selective insect antifeedant and toxic action of ryanoid diterpenes.

In this work, we have studied the antifeedant and insecticidal effects of several natural ryanoid diterpenes. These compounds can be classified in two groups according to their chemical structures: ryanodol/isoryanodol-type (nonalkaloidal type) and ryanodine-type (alkaloidal type) ryanoids. The nonalkaloidal ryanoids were isolated from Persea indica (Lauraceae) while the alkaloidal ryanoids (ryanodines and spiganthines) were isolated from Spigelia anthelmia (Loganiaceae). The effects of these compounds on the feeding behavior and performance (with and without piperonyl butoxide pretreatment) of Spodoptera littoralis larvae and Leptinotarsa decemlineata adults indicate that some strongly deterred these insects, L. decemlineata being less sensitive than S. littoralis. Their antifeedant effects did not parallel their toxic action. Additionally, more than 60% of the nonalkaloidal ryanoids were antifeedants and/or toxic in contrast to 30% of active alkaloidal ones, supporting the hypothesis of a ryanodol-specific mode of action in insects.

Animals↗
PubMed1998

[Aberration of somatic karyotype in normozoospermic males from infertile couples].

During the complex investigation of couple infertility, a group of 40 normozoospermic males having low density of semen was selected. Cytogenetic analysis revealed 2 cases of somatic karyotype aberrations: 47,XYY and 46,XY,t(14;19), and 2 cases of chromosomal polymorphisms: 46,XYq+ i 46,XY,14p+. In the article the mechanism of fertility disturbances evoked by these findings is discussed in aspects of the function of spermatozoa and its genetic material content.

Adult↗
PubMed1997

[Functional and esthetic blepharoplasty].

Functional blepharoplasty is characterized by both esthetic and functional impairment. Proper management requires a meticulous preoperative analysis with special regard to brow position, lid crease and lid fold, levator function, tightness of the canthal ligaments, tarsal plate and orbital septum, because these factors will determine the kind and extent of the operation. In the upper lid the incision depends on the individual situation, while in the lower lid it is routinely done subciliarly. Symmetry should be achieved in each case with regard to several safety guidelines in order to prevent complications.

Adult↗