2,3‐Dihydro‐1‐Benzofuran Derivatives as a Series of Potent Selective Cannabinoid Receptor 2 Agonists: Design,Synthesis, and Binding Mode Prediction through Ligand‐Steered Modeling

We recently discovered and reported a series of N‐alkyl‐isatin acylhydrazone derivatives that are potent cannabinoid receptor 2 (CB₂) agonists. In an effort to improve the druglike properties of these compounds and to better understand and improve the treatment of neuropathic pain, we designed and synthesized a new series of 2,3‐dihydro‐1‐benzofuran derivatives bearing an asymmetric carbon atom that behave as potent selective CB₂ agonists. We used a multidisciplinary medicinal chemistry approach with binding mode prediction through ligand‐steered modeling. Enantiomer separation and configuration assignment were carried out for the racemic mixture for the most selective compound, MDA7 (compound 18 ). It appeared that the S enantiomer, compound MDA104 (compound 33 ), was the active enantiomer. Compounds MDA42 (compound 19 ) and MDA39 (compound 30 ) were the most potent at CB₂. MDA42 was tested in a model of neuropathic pain and exhibited activity in the same range as that of MDA7. Preliminary ADMET studies for MDA7 were performed and did not reveal any problems.     

Emotions, defenses, coping mechanisms, and symptoms.

Used L. A. Gottschalk and G. C. Gleser's (1969) method of content analysis to examine 5-min samples of speech elicited from 6 different groups of Ss: 30 young normal men (mean age 25.7 yrs), 30 normative adults (aged 20–50 yrs), 30 normative schoolchildren (aged 6–26 yrs), 20 adults with psychoneuroses, 44 emotionally disturbed criminal offenders (mean age 25.6 yrs), and 22 acute schizophrenics (aged 21–55 yrs). Ss were given purposely ambiguous standardized instructions simulating the request to free-associate. Findings indicate that displacements and denials in mentally healthy individuals are more likely to function as coping mechanisms in contrast to their function as defenses or symptoms in mentally disordered people. No significant effects of sex, age, intelligence, or state of consciousness were found. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Microstructural and Phase Composition Differences Across the Interfaces in Al/Ti/Al Explosively Welded Clads

The microstructure and phase composition of Al/Ti/Al interfaces with respect to their localization were investigated. An aluminum-flyer plate exhibited finer grains located close to the upper interface than those present within the aluminum-base plate. The same tendency, but with a higher number of twins, was observed for titanium. Good quality bonding with a wavy shape and four intermetallic phases, namely, TiAl₃, TiAl, TiAl₂, and Ti₃Al, was only obtained at the interface closer to the explosive material. The other interface was planar with three intermetallic compounds, excluding the metastable TiAl₂ phase. As a result of a 100-hour annealing at 903 K (630 °C), an Al/TiAl₃/Ti/TiAl₃/Al sandwich was manufactured, formed with single crystalline Al layers. A substantial difference between the intermetallic layer thicknesses was measured, with 235.3 and 167.4 µm obtained for the layers corresponding to the upper and lower interfaces, respectively. An examination by transmission electron microscopy of a thin foil taken from the interface area after a 1-hour annealing at 825 K (552 °C) showed a mixture of randomly located TiAl₃ grains within the aluminum. Finally, the hardness results were correlated with the microstructural changes across the samples.

     

High accuracy FIONA-AFM hybrid imaging

Multi-protein complexes are ubiquitous and play essential roles in many biological mechanisms. Single molecule imaging techniques such as electron microscopy (EM) and atomic force microscopy (AFM) are powerful methods for characterizing the structural properties of multi-protein and multi-protein-DNA complexes. However, a significant limitation to these techniques is the ability to distinguish different proteins from one another. Here, we combine high resolution fluorescence microscopy and AFM (FIONA-AFM) to allow the identification of different proteins in such complexes. Using quantum dots as fiducial markers in addition to fluorescently labeled proteins, we are able to align fluorescence and AFM information to ≥8 nm accuracy. This accuracy is sufficient to identify individual fluorescently labeled proteins in most multi-protein complexes. We investigate the limitations of localization precision and accuracy in fluorescence and AFM images separately and their effects on the overall registration accuracy of FIONA-AFM hybrid images. This combination of the two orthogonal techniques (FIONA and AFM) opens a wide spectrum of possible applications to the study of protein interactions, because AFM can yield high resolution (5-10 nm) information about the conformational properties of multi-protein complexes and the fluorescence can indicate spatial relationships of the proteins in the complexes.     

The cerebral neurobiology of hope and hopelessness

Hope and hopelessness are useful constructs that have been employed by clinicians in theory making regarding the pathogenesis and course of disease and in the application of various psychological and medical treatments to illness. French (1952) and Frank (1968) viewed hope as a necessary motivating force in influencing an individual to try to overcome inner psychological conflicts and seek to resolve a psychoneurosis. Melges and Bowlby (1969) classified the types of hopelessness in psychopathological processes. Perley et al. (1971), using an objective method for content analysis of small samples of speech (Gottschalk 1974), found that elevated hope scores predicted continuation of psychiatric treatment rather than dropping out. Gottschalk et al. (1967, 1969) found that hope scores derived from verbal samples predicted the duration of survival of patients with terminal cancer receiving irradiation treatment (1969) and predicted relatively favorable outcome in psychotherapy (1967).     

A New Route to Macrocycles Possessing the 2,6-Pyridino Subunit via Bis-1,3-Dithianes [1]

Two rigid crown ethers 12 , which possess a terpyridine subunit, are herein prepared by the construction of the middle pyridine moiety via a bis-dithiane precursor. The intermediate diketone and derivatives are sufficiently mobile to permit macrocyclization; then their irreversible conversion to a pyridine nucleus circumvents the inherent structural constraints associated with the synthesis of these macromolecules.