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P Gmeiner

Publications and source records attributed to P Gmeiner.

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

Comparative molecular field analysis of dopamine D4 receptor antagonists including 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113), 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]-1H-pyrrolo-[2,3-b]pyridine (L-745,870), and clozapine.

A CoMFA study was undertaken to elucidate the correlation of biological activity and structural parameters of 25 dopamine D4 antagonists. A special point of interest is that we have included the atypical D4 antagonist clozapine as a structural template for all other compounds. After comparing potential protonation sites at semiempirical (AM1) and ab initio (6-31G(d)) levels of theory, possible conformations of the lead compound 3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 113) were investigated by systematic semiempirical conformational analysis. The final conformation of FAUC 113, which was used as a template for the other compounds in the dataset, was chosen by clustering and rigid body alignment of all conformations to clozapine. The CoMFA applied on the final alignment resulted in a q2cv of 0.739. To elucidate the influence of the absolute orientation of the molecules within the grid space, the entire dataset was systematically rotated (1296 steps) within the lattice. The Gaussian-shaped distribution of the q2cv values spanned the range of 0.699-0.794 and therefore supports the significance of the analysis.

Clozapine↗
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

Enantiopure 4- and 5-aminopiperidin-2-ones: regiocontrolled synthesis and conformational characterization as bioactive beta-turn mimetics.

Starting from aspartic acid, we synthesized lactam-bridged beta- and gamma-amino acid equivalents. Using the 1,4-bis-electrophile 1b as a central intermediate, the 4- and 5-aminopiperidin-2-ones 4 and 8, respectively, were approached by regioselective functionalization and subsequent lactamization. Diastereoselective C-alkylation was performed after N-protection of the lactam functionality when exclusive trans configuration resulting in the formation of 5a-f was observed in the 4-amino series. On the other hand, cis selectivity was typical for the alkylations of the 5-amino lactams 5a,b. To investigate the ability of the lactam building blocks to induce reverse-turn structures by intramolecular hydrogen bonding, the model peptidomimetics 12 and 14 representing Homo-Freidinger lactams of type II and III were prepared from 4a and 8a, respectively. Conformational analyses in dilute solution (1 mM) by IR and NMR spectroscopy at room temperature clearly indicated that the 4-aminopiperidin-2-one derivative 12 predominantly adopts a reverse-turn structure stabilized by a CO-HN hydrogen bond in an 11-membered ring. VT NMR experiments showed a substantial temperature dependency of the terminal NH when Deltadelta(NH)/DeltaT = -6.5 indicated that the amount of intramolecular hydrogen bonding is higher at low temperature. An application in the field of medicinal chemistry was demonstrated. Thus, starting from the Homo-Freidinger lactam 11c and the enantiomer ent-11c, we synthesized the peptidomimetics 15c and 16c and investigated them as lactam-bridged analogues of the dopamine receptor modulating peptide Pro-Leu-Gly-NH(2) (PLG). Both test compounds turned out to enhance significantly the agonist binding of dopamine D2 receptors, when the isomer 15c revealed a potency comparable to the genuine ligand PLG.

Animals↗
PubMed2000

Treatment of N,N-dibenzylamino alcohols with sulfonyl chloride leads to rearranged beta-chloro amines, precursors to beta-amino acids, and not to tetrahydroisoquinolines.

[reaction: see text] Very recently, the unexpected formation of 3-substituted 1,2,3,4-tetrahydroisoquinolines starting from N,N-dibenzyl-protected beta-amino alcohols was reported. The authors claimed that treatment with tosyl chlorides induced intramolecular Friedel-Crafts alkylation. Reexamination of the reactions in our laboratory clearly proved rearranged chloro amines instead of the initially assumed tetrahydoisoquinoline structures. The chloro amines investigated can be employed as highly useful intermediates for an EPC synthesis of beta-amino nitriles and beta-amino acids.

Amines↗
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

Ex-chiral pool synthesis and pharmacological aspects of 3-pyrrolidinylisoxazoles.

Employing the dopamine autoreceptor agonist (-)-3-PPP (3) as well as the cholinergic receptor ligands 4 and 5 as lead compounds the 3-pyrrolidinylisoxazoles 2a,b as well as its optical antipodes ent 2a,b were synthesized from (R)-aspartic acid (6) and (S)-aspartic acid (ent-6), respectively. Pharmacological properties of the target compounds were evaluated employing dopamine D2 receptor binding studies and functional experiments on muscarinic M2 receptors.

Animals↗
PubMed1999

[3H]Pramipexole: a selective radioligand for the high affinity dopamine D2 receptor in bovine striatal membranes.

The characterization of [3H]pramipexole binding to bovine striatal membranes is reported in full experimental detail. According to kinetic experiments, saturation and competition studies a single binding site can be selectively labeled which turned out to be the high affinity D2 receptor. Addition of GPP(NH)P resulted in almost complete loss of specific binding. The bovine D2 subtype shows high sequence identity with the human D2 receptor indicating that the heterologous competition assays are of interest for the evaluation of neurotropic drug candidates. Using the representative D2 agonists (+)-7-OH-DPAT, (-)-3-PPP and (S)-7-dipropylaminotetrahydroindolizine the same rank order of affinities was determined as described for rat striata labeled with [3H]pramipexole, however, the Ki values turned out to be significantly higher. Furthermore, the system facilitates structure activity relationship studied on D2 affinity modulating peptides. Using L-prolyl-L-leucyl-glycinamide as an example a significant increase of specific radioligand binding could be measured.

Animals↗
PubMed1998

Beta-analogs of PLG (L-prolyl-L-leucyl-glycinamide): ex-chiral pool syntheses and dopamine D2 receptor modulating effects.

Starting from (S)- and (R)-aspartic acid enantiomerically pure beta-proline derivatives were synthesized. These chiral building blocks were transformed into beta-analogs of the dopamine receptor modulating peptide PLG. According to dopamine receptor binding studies, significant enhancement of [3H]pramipexole binding was observed for the isomeres 1a,b and 2a-c. The derivative 1b revealed an activity comparable to PLG.

Animals↗