Biomedical subjects

P Luger

Publications and source records attributed to P Luger.

29 records · Page 2Linked to original sources

PubMed1998

Accurate experimental electronic properties of dl-proline monohydrate obtained within 1 Day

A 1-day x-ray diffraction experiment on dl-proline monohydrate was performed at 100 kelvin with synchrotron radiation and a charge-coupled device area detection technique. The accuracy of the charge density distribution and of the related electronic properties extracted from these data is comparable or even superior to the accuracy obtained from a 6-week experiment on dl-aspartic acid with conventional x-ray diffraction methods. A data acquisition time of 1 day is comparable to the time needed for an ab initio calculation on the isolated molecules. This technique renders larger molecular systems of biological importance accessible to charge density experiments.

Journal Article↗

PubMed1997

Crystal structures of the even and odd bolaform amino acid derivatives (11-N-[benzyloxycarbonyl-L-alanyl]aminoundecanoyl)-L-alanyl benzyl ester and (12-N-[benzyloxycarbonyl-L-alanyl]aminododecanoyl)-L-alanyl benzyl ester.

Reaction of two alpha, omega-aminocarboxylic acids with N- and C-protected alanine leads to bolaform compounds with two secondary amide groups on one end and one such group at the other end. Unsymmetric sheet-like structures are formed in the crystals. (11-N-[Benzyloxycarbonyl-L-alanyl] aminoundecanoyl)-L-alanyl benzyl ester (1) and (12-N-[benzyloxycarbonyl-L-alanyl] aminododecanoyl)-L-alanyl benzyl ester (2) form triclinic crystals (spacegroup P1, No.1) with a = 4.917, b = 5.614, c = 29.02 A. alpha = 88.40, beta = 93.50, gamma = 100.21 degrees, Z = 1 (1) and a = 4.954, b = 5.613, c = 30.23 A, alpha = 93.44, beta = 90.07, gamma = 104.15 degrees, Z = 1 (2). The crystal structures were solved via direct methods and refined to R = 0.040 (1) and 0.078 (2) from 2441 and 2725 reflections.

Alanine↗

PubMed1996

New potent azomethine prodrugs of the histamine H3-receptor agonist (R)-alpha-methylhistamine containing a heteroarylphenyl partial structure.

The therapeutic value of histamine H3-receptor ligands is under current investigation. On the basis of recently described diary limine prodrugs of the histamine H3-receptor agonist (R)-alpha-methylhistamine (1) as a series of new azomethine prodrugs containing five- and six-membered heterocycles were synthesized and tested for their in vitro hydrolysis rates and in vivo activity after oral application. It was found that electron-deficient six-membered heterocycles drastically destabilized the imine double bond so that these prodrugs decomposed unsuitably fast. On the contrary, prodrugs containing five-membered heterocycles appeared to be highly effective for the CNS delivery of 1, and a remarkable correlation between chemical structure and pharmacokinetic profile was observed. Particularly (R)-4-fluoro-2-[[N-[1-(1H-imidazol-4-yl)-2-propyl]imino] (1H-pyrrol-2-yl)methyl]phenol (8c), the 2-furanyl analogue 8d, and its 3-furanyl isomer 8e proved to be equipotent to the most potent of recently described halogenated diaryl imine prodrugs of 1. However, in contrast to any other azomethine prodrug, 8c exhibited an incomparably long lasting delivery of 1 in the CNS and can thus be regarded as a 'retard' prodrug. Assuming that a therapeutic indication of histamine H3-receptor agonists will soon be established, these highly potent heteroarylphenyl azomethine prodrugs, which already serve as valuable pharmacological tools, may also become potential drugs in clinical use.

Animals↗

PubMed1995

Synthesis, X-ray crystallography, and pharmacokinetics of novel azomethine prodrugs of (R)-alpha-methylhistamine: highly potent and selective histamine H3 receptor agonists.

Since various neuroregulatory functions of the histamine H3 receptor have been proved during the last few years, the H3 receptor is of current interest. Azomethine derivatives of the highly potent histamine H3 receptor agonist (R)-alpha-methylhistamine (1) were prepared as lipophilic prodrugs to improve the bioavailability of the hydrophilic drug, particularly its entry into the brain. Additionally, azomethine derivatization provides protection against histamine methyltransferase, the major metabolizing enzyme in man, and thus efficiently enhances the bioavailability of 1. The molecular conformations of (R)-2(-)[[N(-)[1-(1H-imidazol-4-yl)-2-propyl]- imino]phenylmethyl]phenol (9a) and (R)-4-fluoro-2(-)[[N(-)[1-(1H-imidazol-4-yl)-2-propyl[imino]- (4-chlorophenyl)methyl]phenol (9p) were determined by X-ray structure analysis. An intramolecular hydrogen bond which is essential for the stability of these azomethines was thereby confirmed. Moreover, the pharmacokinetic parameters of the prodrugs were investigated in vitro as well as in vivo. The halogenated azomethines have an effect following peroral administration in mice, and some of them seem to be highly potent for the central nervous system (CNS) delivery of 1. At present the most potent prodrug of 1 is (R)-4-chloro-2(-)[[N(-)[1-(1H-imidazol-4-yl)-2-propyl]imino](4- chlorophenyl)methyl]phenol (9q), reaching by far the highest CNS level of 1 (Cmax = 71 ng/g). Prodrugs of this type are not only valuable pharmacological tools but may also become H3 histaminergic drugs for therapeutic use.

Animals↗

PubMed1992

Synthesis, absolute configuration, stereoselectivity, and receptor selectivity of (alpha R, beta S)-alpha,beta-dimethylhistamine, a novel high potent histamine H3 receptor agonist.

Depending on the selected synthetic pathway, structural variations of the neurotransmitter histamine led to mixtures of alpha,beta-dimethylhistamines as well as to the corresponding pure optical isomers. One of these isomers, namely (alpha R,beta S)-alpha,beta-dimethylhistamine, proved to be a highly potent H3 receptor agonist with exceptional receptor selectivity. The absolute configuration of the compound was determined by X-ray structure analysis of its dihydrobromide using the anomalous dispersion of bromine. The optical purity of both enantiomers of erythro-alpha,beta-dimethylhistamine was checked by 1HNMR investigations after acylation of the amines with (R)-2-methoxy-2-phenylacetyl chloride. As expected H3 receptors distinguish in a very strong way between the title compound and its alpha S,beta R-configured enantiomer. The agonistic potency of the latter is 2 orders of magnitude lower than the potency of (alpha R,beta S)-alpha,beta-dimethylhistamine.

Animals↗

PubMed1991

Novel chiral H3-receptor agonists.

Several alkyl-substituted histamine derivatives have been synthesized and investigated for their agonistic potency on three classes of histamine receptors. While all investigated compounds are full agonists at H3-receptors their relative potency vs. histamine is strongly varying and culminates in alpha R, beta S-dimethylhistamine which is a highly potent and selective H3-receptor agonist.

Animals↗

PubMed1990

Specific bradycardic agents. 1. Chemistry, pharmacology, and structure-activity relationships of substituted benzazepinones, a-new class of compounds exerting antiischemic properties.

Structural modification of the calcium-antagonist verapamil (1) by replacement of the lipophilic alpha-isopropylacetonitrile moiety by various heterocyclic ring systems has led to a new class of cardiovascular compounds which are characterized by a specific bradycardic activity. These agents reduce heart rate without binding to classical calcium channels or beta-adrenoceptors, interacting instead specifically with structures at the sino atrial node. Therefore they have also been termed sinus node inhibitors. The prototype falipamil (2) has been submitted to further optimization mainly by manipulation of the phthalmidine moiety. This has resulted in a second generation of specific bradycardic agents with increased potency and selectively and prolonged duration of action represented by the benzazepinone-derivative UL-FS 49 (4). Structure-activity relationships within this novel class of compounds have revealed a marked dependence of activity on the substitution pattern of the aromatic rings, the nature of the central nitrogen atom, and the length of the connecting alkyl chains. The crucial role of the benzazepinone ring for bradycardic activity can be best explained by its special impact on the overall molecular conformation.

Animals↗

PubMed1990

Epimerization of erythromycin derivatives.

Dirithromycin (3) isomerizes upon dissolution in different solvents. From X-ray analysis of V-T 108, an analogue of dirithromycin, and comparative 1H and 13C NMR, and MS data, the isomer of dirithromycin was confirmed to be the C-16-(S)-epimer. The ratio of the two epimers at equilibrium conditions was approximately 8:2 (R/S) in methanol at room temperature.

Anti-Bacterial Agents↗

PubMed1984

X-ray analysis of 3-O-(6-O-acetyl-2,4-diazido-3-O-benzyl-2,4-dideoxy-alpha-D-gl glucopyranosyl)-1,6-anhydro-2,4-diazido-2,4-dideoxy-beta-D- glucopyranose, a disaccharide having an unusual alpha-D-(1----3) linkage.

The crystal structure of 3-O-(6-O-acetyl-2,4-diazido-3-O-benzyl-2,4-dideoxy-alpha-D- glucopyranosyl)-1,6-anhydro- 2,4-diazido-2,4-dideoxy-beta-D-glucopyranose, C21H24N12O7, mol. wt. 556.5, was investigated by X-ray analysis. The disaccharide crystallizes in the triclinic space group P1, with a = 889.3(5), b = 869.6(5), and c = 999.5(6) pm, and alpha = 105.83(4) degrees, beta = 116.22(4) degrees, gamma = 88.42(4) degrees, Z = 1, and rho = 1.394 g.cm-3. Phase determination failed with direct methods, but, as the 1,6-anhydride component of the molecule was already known from a previous structure analysis, the vector-search method could be applied in solving the structure. Diffractometer data were refined to an R value of 0.063 (Rw = 0.080) for 2102 observed reflections. The anhydro-bridged system has a distorted 1C4(D) conformation, in agreement with that of other anhydropyranoses so far investigated. A comparison shows that, for the specific kind of distortion, mainly the anti-reflex effect is responsible, whereas 1,3-diaxial interactions have a minor influence. The nonbridged ring adopts an almost perfect 4C1(D) conformation. The anomeric effect is observed in both of the sugar-ring systems in terms of bond-length shortening. The disaccharide has an alpha-D-Glc-4C1-(1a----3e)-D-Glc-1C4 glycosidic linkage. No previous X-ray investigation of a compound of this type is known. The pyranoid rings are almost perpendicular to each other. The phi, psi angles of the glycosidic linkage are +78.1(5) and -86.0(4) degrees.(ABSTRACT TRUNCATED AT 250 WORDS)

Crystallography↗

PubMed1984

Crystal and molecular structures of 6-O-acetyl-2,3,4-trideoxy-alpha-DL-glycero-hex-2-enopyranose and 3-O-(6-O-acetyl-2,3,4-trideoxy-alpha-L-glycero-hex-2-enopyranosyl++ +)-1,2 ;5,6-di-O-isopropylidene-alpha-D-glucofuranose.

6-O-acetyl-2,3,4-trideoxy-alpha-DL-glycero-hex-2-enopyranose (1) and 3-O-(6-O-acetyl-2,3,4-trideoxy-alpha-L-glycero-hex-2-enopyranosyl) -1,2;5,6-di-O-isopropylidene-alpha-D-glucofuranose (2) have been investigated by X-ray diffraction methods. Compound 1 crystallises in the monoclinic system, space group P21/a, with cell constants a = 21.123(5), b = 4.439(2), c = 10.085(2) A, and beta = 110.22(2) degrees. Compound 2 crystallises in the orthorhombic system, space group P212121, with cell constants a = 22.110(6), b = 11.651(4), and c = 8.658(3) A. The intensity data were collected in a four-circle automatic diffractometer, with 1488 reflections for 1, and 2151 for 2. The structures were solved by direct methods. The atomic parameters were refined in an anisotropic mode by the full-matrix, least-squares procedure against 1065 and 1884 observed reflections for 1 and 2, respectively, giving R = 0.046 for each compound. The 2-enopyranose rings in 1 and 2 adopt half-chair conformations (H), and that in 2 is markedly deformed. The 1,2-dioxolane ring in 2 has an envelope (E) conformation, whereas the 5,6-dioxolane ring is dynamically disordered and can be represented by a conformational hybrid (E + P). The alpha-D-glucofuranose ring in 2 has a twist conformation (T). The glycoside bond in 2 is characterized by phi and psi torsion angles of 47(2) degrees and 32(2) degrees, respectively.

Crystallography↗

PubMed1984

Conformational analysis of the antiulcer drug pirenzepine. X-ray investigations, molecular mechanics and quantum mechanical calculations and comparisons with structurally or pharmacologically related compounds.

The crystal structures of the antiulcer drug 5,11-dihydro-11-[(4-methyl-1-piperazinyl) acetyl]-6H-pyrido[2,3-b] [1,4]benzodiazepin-6-one dihydrochloride (pirenzepine dihydrochloride, L-S 519 CL 2, Gastrozepin) and its monoprotonated form (pirenzepine monohydrochloride, L-S 519 CL) were determined by X-ray analysis. Molecular mechanics (MMPI) and semiempirical quantum chemical (MNDO) calculations showed that the calculated minimum energy conformations of the tricycle and of the exocyclic amide group are in agreement with the crystal structures. The conformational energies of pirenzepine as a function of four important torsional angles were calculated using different semiempirical quantum chemical methods with the CNDO/2 (complete neglect of differential overlap)-, MNDO (modified neglect of diatomic overlap)- and PCILO (perturbative configuration interaction using localized orbitals)-approximations. The conformation of one local energy minimum corresponds closely to the crystal structure of pirenzepine monohydrochloride. This conformation has a spatial arrangement which is analogous to a single consistent conformation known from the literature of 24 anticholinergic agents determined from their crystal structures by a computer graphics analysis. On the other hand there are no structural relationships of any low energy conformation of pirenzepine to conformations of other classes of tricyclic compounds which could rationalize their antidepressant, neuroleptic or antihistaminic activity. This finding explains the absence of any central effect of pirenzepine following intracerebral application. The computational elucidation of the conformational requirements for the interaction with the muscarinic receptors may be helpful for the interpretation of the selectivity of pirenzepine within the muscarinic system.

Antidepressive Agents, Tricyclic↗