Biomedical subjects

J M Rollinger

Publications and source records attributed to J M Rollinger.

8 recordsLinked to original sources

PubMed2006

Integrated in silico tools for exploiting the natural products' bioactivity.

Whereas computational methods for molecular design are well established in medicinal chemistry research, their application in the field of natural products is still not exhaustively explored. This article gives a short introduction into both the potential for the application of computer-assisted approaches, such as pharmacophore modelling, virtual screening, docking, and neural networking to efficiently access the bioactive metabolites, and the requirements and limitations related to this specific field. The challenge is which selection criteria and/or multiple filtering tools to apply for a target-oriented isolation of potentially bioactive secondary metabolites. Application examples are provided where in silico tools and classical methods used by natural product scientists are used in an effort to maximize their efficacy in drug discovery. Thus, integrated computer-assisted strategies may help to process the huge amount of available structural and biological information in a reasonably short time for a straightforward search of bioactive natural products.

Computer-Aided Design↗

PubMed2006

Strategies for efficient lead structure discovery from natural products.

This investigation aims to evaluate strategies for an efficient selection of bioactive compounds from the multitude and biodiversity of the plant kingdom. Statistics prove natural products (NPs) as a source leading most consistently to successful development of new drugs. However, there are several reasons why the interest in finding bioactive NPs has generally declined at several major pharmaceutical companies. Their substantial argument is that the research in this field is time-consuming, highly complex and ineffective. A more rational and economic search for new lead structures from nature must therefore be a priority in order to overcome these problems. In this paper, different strategies are described to exploit the molecular diversity of bioactive secondary metabolites, namely classical pharmacognostic approaches and computational methods. The latter include various data mining tools, like virtual screening filtering experiments using pharmacophore models, docking studies, and neural networks, which help to establish a relationship between chemical structure and biological activity. The strengths and weaknesses of these methods will be shown in this review. Focusing on selected targets within the arachidonic acid cascade (phospholipase A(2), 5-lipoxygenase, cyclooxygenase-1 and -2), several studies of successful discoveries in the field of anti-inflammatory NPs were scrutinized for the applied strategies. Both the compilation of relevant published data and recent studies supported by our own research clearly demonstrate the benefits of the synergistic effect of a hybridization of these strategies for an effective drug discovery from natural ingredients.

Anti-Inflammatory Agents↗

PubMed2005

Application of the in combo screening approach for the discovery of non-alkaloid acetylcholinesterase inhibitors from Cichorium intybus.

Because of the direct correlation of cholinergic deficit and the severity of dementia, Alzheimer's disease is preferentially treated with acetylcholinesterase (AChE) inhibitors to supplement the acetylcholine level. In this study we focused on non-alkaloid AChE inhibitors from natural sources in order to discover new lead structures. In the course of in vitro extract screening of Tyrolean plants using an enzyme assay with Ellman's reagent, the dichloromethane extract of chicory roots (Cichorium intybus L.) showed a pronounced inhibitory effect on AChE. At a concentration of 1 mg extract/ml an inhibition of 70% was measured. Based on a 3D multi-conformational molecular-structure database consisting of secondary metabolites from C. intybus known from the relevant literature, virtual screening filtering experiments were conducted using both a feature-based pharmacophore model and a docking procedure. Some low molecular weight sesquiterpenoids exhibited distinct interactions with the pharmacophore model. In order to verify the applicability of this computer-aided strategy, an activity-guided fractionation of the chicory root extract was performed, which resulted in the isolation of two sesquiterpene lactones, 8-deoxylactucin and lactucopicrin, showing significant and dose-dependent inhibitory activity on AChE (IC(50) of 308.1 microM [CI(95) 243.9 - 405.3 microM] and 150.3 microM [CI(95) 100.8 - 188.1 microM], respectively). The two isolates were correctly predicted within the virtual screening process which corroborates the potential of the computer-assisted in combo screening approach for the discovery of the anti-cholinesterase compounds from C. intybus.

Acetylcholinesterase↗

PubMed2001

Polymorphism of racemic felodipine and the unusual series of solid solutions in the binary system of its enantiomers.

The aim of this study was to investigate the binary phase diagram and the polymorphism and pseudopolymorphism of racemic and enantiomeric felodipine, including their spectroscopic and thermodynamic properties. Different crystal forms were obtained by crystallization from solvents or from the annealed melt and investigated by thermal analysis (hot stage microscopy, differential scanning calorimetry, thermogravimetric analysis), spectroscopic methods (Fourier transform infrared-and Fourier transform-Raman spectroscopy), and X-ray powder diffractometry. The binary melting phase diagram was constructed based on thermoanalytical investigations of quantitative mixtures of (+)- and (+/-)-felodipine. Two polymorphic forms of racemic felodipine, mod. I (mp, approximately 145 degrees C) and mod. II (mp, approximately 135 degrees C), as well as an acetone solvate (S(Ac )) were characterized. Melting equilibria of felodipine crystal forms decrease due to thermal decomposition. Enantiomeric felodipine was found to be dimorphic (En-mod. I: mp, approximately 144 degrees C; En-mod. II: mp, approximately 133 degrees C). Evaluation of the binary system of (+)- and (-)-felodipine results in the formation of a continuous series of mixed crystals between the thermodynamically stable and higher melting modifications, mod. I and En-mod. I. Their unusual curve course, termed as Roozeboom Type 2 b, passes through a maximum in the racemic mixture and is flanked by a minimum at 20% and at 80% (+)-felodipine. From the thermodynamic parameters, racemic mod. I and II are monotropically related. In contrast to S(Ac), the thermodynamically unstable mod. II shows a considerable kinetic stability. Because its crystallization is badly reproducible, the use of mod. II is not advisable for processing. However, desolvation of S(Ac) leads to a profitable crystal shape of mod. I, representing a pseudoracemate by definition.

Calcium Channel Blockers↗

PubMed2000

Energy/temperature diagram and compression behavior of the polymorphs of D-mannitol.

Three modifications of D-mannitol were produced and investigated: mod. I (mp 166.5 degrees C, heat of fusion 53.5 kJ mol(-1)), mod. II (mp 166 degrees C, heat of fusion 52.1 kJ mol(-1)), and mod. III (mp incongruent 150-158 degrees C, heat of transition, III to I 0.2 kJ mol(-1)). The measured densities are 1.490 +/- 0.000 g cm(-3) [95% confidence interval (CI)] for mod. I, 1.468 +/- 0.002 g cm(-3) (95% CI) for mod. II, and 1.499 +/- 0.004 g cm(-3) (95% CI) for mod. III. It was possible to relate the different modifications given in the literature to one of the three pure crystal forms or to mixtures of two or all three modifications. The thermodynamic relationship among the crystal forms is represented in a semi-schematic energy/temperature diagram. From these data we can conclude that mod. III is thermodynamically stable at absolute zero. It is enantiotropically related to mod. I and mod. II. FTIR and Raman spectra, differential scanning calorimetry curves, and X-ray powder patterns of these crystal forms are depicted for doubtless assignment in the future. The water uptake of the three modifications at 92% relative humidity and 25 degrees C is less than 1%. The differences of the heat capacities and the heats of solution between mod. II and III are not significant, whereas mod. I shows small significant differences compared with the other modifications. In addition, compaction studies of these crystal forms were performed by means of an instrumented hydraulic press. The results show that mod. III should have the best tableting behavior under these conditions.

Calorimetry, Differential Scanning↗

PubMed1999

An evaluation of the transition temperature range of super-elastic orthodontic NiTi springs using differential scanning calorimetry.

Differential scanning calorimetry (DSC) was used to determine the transition temperature ranges (TTR) of four types of super-elastic orthodontic nickel-titanium coil springs (Sentalloy). A knowledge of the TTR provides information on the temperature at which a NiTi wire or spring can assume superelastic properties and when this quality disappears. The spring types in this study can be distinguished from each other by their characteristic TTR during cooling and heating. For each tested spring type a characteristic TTR during heating (austenite transformation) and cooling (martensite transformation) was evaluated. The hysteresis of the transition temperature, found between cooling and heating, was 3.4-5.2 K. Depending on the spring type the austenite transformation started (As) at 9.7-17.1 degrees C and finished (Af) at 29.2-37 degrees C. The martensite transformation starting temperature (Ms) was evaluated at 32.6-25.4 degrees C, while Mf (martensite transformation finishing temperature) was 12.7-6.5 degrees C. The results show that the springs become super-elastic when the temperature increases and As is reached. They undergo a loss of super-elastic properties and a rapid decrease in force delivery when they are cooled to Mf. For the tested springs, Mf and As were found to be below room temperature. Thus, at room temperature and some degrees lower, all the tested springs exert super-elastic properties. For orthodontic treatment this means the maintenance of super-elastic behaviour, even when mouth temperature decreases to about room temperature as can occur, for example, during meals.

Body Temperature↗

PubMed1997

Binary system of (R)- and (S)-nitrendipine--polymorphism and structure.

Three monotropically related modifications of (RS)-nitrendipine (RS-NTD) were investigated. With the aid of the optical antipodes of NTD, it was possible to construct a binary phase diagram, from which it is obvious that the thermodynamically stable mod. I of RS-NTD (mp 156-158.5 degrees C, heat of fusion 41.1 +/- 0.2 kJ mol-1) is a racemic compound, while mod. II (mp 130-134 degrees C, heat of fusion 29.4 kJ mol-1) and mod. III (mp 124-126 degrees C, heat of fusion 27.2 kJ mol-1) occur as conglomerates of different modifications of R- and S-NTD. The eutectic points (calculated) are at 150 degrees C and at 19% and 81% molar fraction of an enantiomer, respectively. Two modifications of the enantiomers are characterized (En-mod. I, thermodynamically stable form, mp 156-158 degrees C, heat of fusion 34.5 +/- 1.3 kJ mol-1 and En-mod. III, mp 121 degrees C), whereas a third modification (En-mod. II) must be hypothesized pursuant to the phase diagram (mp ca. 152 degrees C). IR spectra, DSC curves, and X-ray powder diffractograms of the different phases are described. The crystal structure of the enantiomer En-mod. I is reported (monoclinic, P2(1), density 1.346 g cm-3) and compared with the X-ray structure of the racemic compound (monoclinic, P2(1)/c, density 1.356 g cm-3). A comparison with similar studies on nimodipine has been made to emphasize the parallels to a substance of this chemical group.

Calcium Channel Blockers↗

PubMed1991

(-)-N,N'-but-2-ene-1,4-diylbimorphinans.

N,N'-But-2-ene-1,4-diylbimorphinans 1-3 have been synthesized and pharmacologically evaluated. Bimorphinans 1 and 3 show opioid antagonist activity and preference for mu and kappa opioid receptors in mouse vas deferens and guinea pig ileum preparations.

Animals↗