Synthesis of a novel series of tetracyclic opioid antagonists incorporating an 8-aminobicyclo[3.2.1]oct-6-ene sub-unit

The bridged bicyclo[3.2.1]oct-ene and -ane amines 9-13 have been prepared via [3+2]cycloaddition of allylic alcohols 6 to alkynes 7, and assessed as ligands at opioid receptors. Amine 10b is a potent antagonist at μ receptors.     

The use of sweep-frequency excitation for unsteady pressure measurement

The use of sweep-frequency excitation for rapid measurement of time-dependent pressures on wind-tunnel models is examined. Results obtained from two different wind-tunnels covering the Mach number range from 0.2 to 0.85, and a wide range of flow conditions, are compared with measurements made using the slower, traditional method of discrete-frequency excitation. It is concluded that the sweep-frequency excitation method can reduce testing time in certain flow conditions with no significant loss in accuracy.List of symbols M Mach number - p broadband rms local static pressure - q 12u ² (dynamic pressure) - R(Cp/) real (in-phase) part of oscillatory Cp/ - I(Cp/) imaginary (in-quadrature) part of oscillatory Cp/ - x/c chord station - wing incidence - canard or wing oscillatory amplitude (plotted in radians unless otherwise stated) - spanwise station - _c canard static incidence - _c canard effective incidence ( _c = 1.89 + _c –0.6) - (T) function of time - ² coherence function The coherence function between two signals x(f), y(f) is defined as - where - G _xy (f) = cross spectral density function between x and y - G _xx (f) = auto spectral density function of x - G _yy (f) = auto spectral density function of y - f = frequency     

Development and application of hybrid structure based method for efficient screening of ligands binding to G-protein coupled receptors

G-protein coupled receptors (GPCRs) comprise a large superfamily of proteins that are targets for nearly 50% of drugs in clinical use today. In the past, the use of structure-based drug design strategies to develop better drug candidates has been severely hampered due to the absence of the receptor’s three-dimensional structure. However, with recent advances in molecular modeling techniques and better computing power, atomic level details of these receptors can be derived from computationally derived molecular models. Using information from these models coupled with experimental evidence, it has become feasible to build receptor pharmacophores. In this study, we demonstrate the use of the Hybrid Structure Based (HSB) method that can be used effectively to screen and identify prospective ligands that bind to GPCRs. Essentially; this multi-step method combines ligand-based methods for building enriched libraries of small molecules and structure-based methods for screening molecules against the GPCR target. The HSB method was validated to identify retinal and its analogues from a random dataset of ∼300,000 molecules. The results from this study showed that the 9 top-ranking molecules are indeed analogues of retinal. The method was also tested to identify analogues of dopamine binding to the dopamine D2 receptor. Six of the ten top-ranking molecules are known analogues of dopamine including a prodrug, while the other thirty-four molecules are currently being tested for their activity against all dopamine receptors. The results from both these test cases have proved that the HSB method provides a realistic solution to bridge the gap between the ever-increasing demand for new drugs to treat psychiatric disorders and the lack of efficient screening methods for GPCRs. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Differentiation of recurrent brain tumor versus radiation injury using diffusion tensor imaging in patients with new contrast-enhancing lesions

BACKGROUND AND PURPOSE: The purpose of this study was to assess the use of diffusion tensor imaging (DTI) in the evaluation of new contrast-enhancing lesions and perilesional edema in patients previously treated for brain neoplasm in the differentiation of recurrent neoplasm from treatment-related injury. METHODS: Twenty-eight patients with new contrast-enhancing lesions and perilesional edema at the site of previously treated brain neoplasms were retrospectively reviewed. Nine directional echoplanar DTIs with b=1000 s/mm(2) were obtained using a single-shot spin-echo echoplanar imaging. Standardized regions of interest were manually drawn in several regions. Mean apparent diffusion coefficient (ADC), fractional anisotropy (FA) and eigenvalue indices (lambda( parallel) and lambda( perpendicular)) and their ratios relative to the contralateral side were compared in patients with recurrent neoplasm versus patients with radiation injury, as established by histological examination or by clinical course, including long-term imaging studies and magnetic resonance spectroscopy. RESULTS: The ADC values in the contrast-enhancing lesions were significantly higher (P=.01) for the recurrence group (range=1.01 x 10(-3) to 1.66 x 10(-3) mm(2)/s; mean+/-S.D.=1.27+/-0.15) than for the nonrecurrence group (range=0.9 x 10(-3) to 1.31 x 10(-3) mm(2)/s; mean+/-S.D.=1.12+/-0.14). The ADC ratios in the white matter tracts in perilesional edema trended higher (P=.09) in treatment-related injury than in recurrent neoplasm (mean+/-S.D.=1.85+/-0.30 vs. 1.60+/-0.27, respectively). FA ratios were significantly higher in normal-appearing white matter (NAWM) tracts adjacent to the edema in the nonrecurrence group (mean+/-S.D.=0.89+/-0.15) than in those in the recurrence group (mean+/-S.D.=0.74+/-0.14; P=.03). Both eigenvalue indices lambda( parallel) and lambda( perpendicular) were significantly higher in contrast-enhancing lesions in the recurrence group than in those in the nonrecurrence group (P=.02). As well, both eigenvalue indices lambda( parallel) and lambda( perpendicular) were significantly higher in perilesional edema than in normal white matter (P<.01 and P<.001, respectively) in both groups. CONCLUSION: The assessment of diffusion properties, especially ADC values and ADC ratios, in contrast-enhancing lesions, perilesional edema and NAWM adjacent to the edema in the follow-up of new contrast-enhancing lesions at the site of previously treated brain neoplasms may add to the information obtained by other imaging techniques in the differentiation of radiation injury from tumor recurrence.     

Forests, colorings and acyclic orientations of the square lattice

There is no known polynomial time algorithm which generates a random forest or counts forests or acyclic orientations in general graphs. On the other hand, there is no technical reason why such algorithms should not exist. These are key questions in the theory of approximately evaluating the Tutte polynomial which in turn contains several other specializations of interest to statistical physics, such as the Ising, Potts, and random cluster models.Here, we consider these problems on the square lattice, which apart from its interest to statistical physics is, as we explain, also a crucial structure in complexity theory. We obtain some asymptotic counting results about these quantities on then ×n section of the square lattice together with some properties of the structure of the random forest. There are, however, many unanswered questions.Supported by a grant from D.G.A.P.A.Supported in part by Esprit Working Group No. 21726, RAND2.     

New approaches for neutron depth profiling

The scope of NDP can be expanded by measuring (via time-of-flight) the kinetic energies of the recoils emitted from (n,p) or (n,) reactions. When they occur inside a solid, the energies of the emerging recoils reveal depth from which they originated. The Recoil Nucleus Time-of-Flight NDP (RN-TOF-NDP) technique can reveal the depth distribution of some isotopes (e.g.,¹⁰B,²¹⁰Bi) with a resolution of a few Å. Furthermore, it is possible to detect atomic and molecular species ejected at the surface site where the recoil emerges from the solid. This paper discusses the methodology for RN-TOF-NDP and its applications including surface analysis based on atomic and molecular ions codesorbed with the recoils.     

Chain twisting in long-chain aliphatic compounds and polyethylene

Rate parameters for dielectric relaxation and the thermal properties of long-chain molecular systems are shown to provide evidence for chain twisting at chain lengths shorter than previously suggested. Comparison of the temperatures of maximum absorption at 1 Hz for mechanical and dielectric relaxation suggests that the underlying motion is not the same for the two observed quanties. The evidence for relaxation in polyethylene is shown to be compatible with this suggestion.     

Three-dimensional quantitative structure-property relationship (3D-QSPR) models for prediction of thermodynamic properties of polychlorinated biphenyls (PCBs): enthalpy of vaporization

Three-dimensional Quantitative Structure-Property Relationship (QSPR) models have been derived using Comparative Molecular Field Analysis (CoMFA) to correlate the vaporization enthalpies of a representative set of polychlorinated biphenyls (PCBs) at 298.15 K with their CoMFA-calculated physicochemical properties. Various alignment schemes, such as inertial, as is, and atom fit, were employed in this study. The CoMFA models were also developed using different partial charge formalisms, namely, electrostatic potential (ESP) charges and Gasteiger-Marsili (GM) charges. The most predictive model for vaporization enthalpy (Delta(vap)H(m)(298.15 K)), with atom fit alignment and Gasteiger-Marsili charges, yielded r2 values 0.852 (cross-validated) and 0.996 (conventional). The vaporization enthalpies of PCBs increased with the number of chlorine atoms and were found to be larger for the meta- and para-substituted isomers. This model was used to predict Delta(vap)H(m)(298.15 K) of the entire set of 209 PCB congeners.