The anxiolytic effects of midazolam during anticipation to pain revealed using fMRI

BACKGROUND AND PURPOSE: Functional neuroimaging can distinguish components of the pain experience associated with anticipation to pain from those associated with the experience of pain itself. Anticipation to pain is thought to increase the suffering of chronic pain patients. Inappropriate anxiety, of which anticipation is a component, is also a cause of disability. We present a pharmacological functional magnetic resonance imaging (fMRI) study in which we investigate the selective modulation by midazolam of brain activity associated with anticipation to pain compared to pain itself. METHODS: Eight right-handed male volunteers underwent fMRI combined with a thermal pain conditioning paradigm and midazolam (30 mug/kg) or saline administration on different occasions, with order randomized across volunteers. Volunteers learned to associate a colored light with either painful, hot stimulation or nonpainful, warm stimulation to the back of the left hand. RESULTS: Comparison of the period during thermal stimulation (pain-warm) revealed a network of brain activity commonly associated with noxious stimulation, including activities in the anterior cingulate cortex (ACC), the bilateral insular cortices (anterior and posterior), the thalamus, S1, the motor cortex, the brainstem, the prefrontal cortex and the cerebellum. Comparison of the periods preceding thermal stimulation (anticipation to pain-anticipation to warm) revealed activity principally in the ACC, the contralateral anterior insular cortex and the ipsilateral S2/posterior insula. Detected by a region-of-interest analysis, midazolam reduced the activity associated specifically with anticipation to pain while controlling for anticipation to warm. This was most significant in the contralateral anterior insula (P<.05). There were no significant drug effects on the activity associated with pain itself. CONCLUSION: In identifying a pharmacological effect on activity preceding but not during pain, we have successfully demonstrated an fMRI assay that can be used to study the action of anxiolytic agents in a relatively small cohort of humans.     

Quantum Dot-Catalyzed Photoreductive Removal of Sulfonyl-Based Protecting Groups

This Communication describes the use of CuInS₂/ZnS quantum dots (QDs) as photocatalysts for the reductive deprotection of aryl sulfonyl-protected phenols. For a series of aryl sulfonates with electron-withdrawing substituents, the rate of deprotection for the corresponding phenyl aryl sulfonates increases with decreasing electrochemical potential for the two electron transfers within the catalytic cycle. The rate of deprotection for a substrate that contains a carboxylic acid, a known QD-binding group, is accelerated by more than a factor of ten from that expected from the electrochemical potential for the transformation, a result that suggests that formation of metastable electron donor–acceptor complexes provides a significant kinetic advantage. This deprotection method does not perturb the common NHBoc or toluenesulfonyl protecting groups and, as demonstrated with an estrone substrate, does not perturb proximate ketones, which are generally vulnerable to many chemical reduction methods used for this class of reactions.     

Quantum Dot‐Catalyzed Photoreductive Removal of Sulfonyl‐Based Protecting Groups

This Communication describes the use of CuInS₂/ZnS quantum dots (QDs) as photocatalysts for the reductive deprotection of aryl sulfonyl‐protected phenols. For a series of aryl sulfonates with electron‐withdrawing substituents, the rate of deprotection for the corresponding phenyl aryl sulfonates increases with decreasing electrochemical potential for the two electron transfers within the catalytic cycle. The rate of deprotection for a substrate that contains a carboxylic acid, a known QD‐binding group, is accelerated by more than a factor of ten from that expected from the electrochemical potential for the transformation, a result that suggests that formation of metastable electron donor–acceptor complexes provides a significant kinetic advantage. This deprotection method does not perturb the common NHBoc or toluenesulfonyl protecting groups and, as demonstrated with an estrone substrate, does not perturb proximate ketones, which are generally vulnerable to many chemical reduction methods used for this class of reactions.     

Glycoconjugated Metallohelices have Improved Nuclear Delivery and Suppress Tumour Growth In Vivo

Monosaccharides are added to the hydrophilic face of a self‐assembled asymmetric Fe^II metallohelix, using CuAAC chemistry. The sixteen resulting architectures are water‐stable and optically pure, and exhibit improved antiproliferative selectivity against colon cancer cells (HCT116 p53^+/+) with respect to the non‐cancerous ARPE‐19 cell line. While the most selective compound is a glucose‐appended enantiomer, its cellular entry is not mainly glucose transporter‐mediated. Glucose conjugation nevertheless increases nuclear delivery ca 2.5‐fold, and a non‐destructive interaction with DNA is indicated. Addition of the glucose units affects the binding orientation of the metallohelix to naked DNA, but does not substantially alter the overall affinity. In a mouse model, the glucose conjugated compound was far better tolerated, and tumour growth delays for the parent compound (2.6 d) were improved to 4.3 d; performance as good as cisplatin but with the advantage of no weight loss in the subjects.     

Molecular modeling of polymers, 14 quantitative structure-property relationship analyses of multicomponent systems containing polymers

One general class of polymer modeling applications involves materials which are large, in terms of molecular degrees of freedom, and poorly defined in terms of composition and morphology. Such materials are often multicomponent with respect to number of distinct polymers, fillers, additives, etc. Two obstacles limit the modeling of these materials. First, one normally does not have any idea about the key physicochemical molecular properties governing the system. Second, the functional dependence of the target properties of the material upon the key physicochemical molecular properties is usually totally unknown. Torsion angle unit (TAU) theory, a molecular decomposition technique, permits an arbitrarily large number of physicochemical properties to be computed in an open-ended fashion, and thus addresses the first problem. Genetic function approximation (GFA) analysis tackles the second problem by efficiently exploring any desired number of functional relationships between target properties and physicochemical molecular properties. Case studies of (TAU theory)-(GFA analysis) applications to estimate glass, Tg, and crystal-melt, Tm, transition temperatures will be described.     

Hydrogenation enthalpimetry--I: microcomputer-assisted calibration and data-acquisition

A calorimetric device is described which permits enthalpimetric determination of unsaturated hydrocarbons through the enthalpy change for their catalytic hydrogenation. Samples with weights from < 1 to about 20 mg can be analysed with a mean error of about 2%. The method makes extensive use of digital electronics and is well suited to routine automated determination of unsaturation. The principal drawback is lack of specificity.     

Reactivity of tetrahydrochromeno[2,3‐b]indoles: chromic indicators of cyanide

The synthesis and reactivity of a tetrahydrochromeno[2,3‐b]indoles are reported. Evidence for reversible ring‐opening is based on H/D exchange and trapping experiments. These compounds readily undergo reaction with tetra‐n‐butylammonium cyanide. The cyanide reaction is 10–100× faster when the solution is irradiated with 350 nm light. Reaction with trimethylsilyl cyanide occurs only with UV irradiation demonstrating photoreactivity. The rate of tetrahydrochromeno[2,3‐b]indole ring‐opening is greater for (i) Me substitution at the hemiaminal carbon (compared to Ph), and (ii) substitution of fluorine at the 9‐position of the indole. Under acidic conditions, the ring‐opened indolium ion is observed. Copyright © 2013 John Wiley & Sons, Ltd.     

Photophysical effect of the coordination of water by ruthenium(II) bipyridyl complexes containing hemilabile phosphine-ether ligands

A substantial concentration-dependent red shift of the absorption and emission spectra (77 K) of [Ru(bpy)(2)(POMe-P,O)](2+) (1) (POMe = (2-methoxyphenyl)diphenylphosphine) is reported. NMR experiments show this shift to be due to equilibration of 1 with an aquo complex (1b) (K(eff) = (6 +/- 3) x 10(-3)) that forms upon displacement of the coordinated ether in the hemilabile POMe ligand. The excited-state lifetimes of 1 and 1b at 77 K in solid 2:1 ethanol/acetone solution are tau = 2.13 +/- 0.02 and 1.95 +/- 0.02 mus, respectively. The preparation and X-ray crystal structure of a related complex, [Ru(bpy)(2)(PO(i)Pr-P)(OH(2))](PF(6))(2) (2b) (PO(i)Pr-P = (2-(2-propoxy)phenyl)diphenylphosphine), is also reported. In solution, this species exists as an equilibrium mixture of complexes that cannot be readily separated. This species also has concentration-dependent absorption spectra in 2:1 ethanol/acetone solution, with a significant red shift (20 nm) at lower concentrations.     

Polar,non-coordinating ionic liquids as solvents for the alternating copolymerization of styrene and CO catalyzed by cationic palladium catalysts

The palladium-catalyzed copolymerization of styrene and CO in an ionic liquid solvent, 1-hexylpyridinium bis(trifluoromethanesulfonyl)imide, gave improved yields and increased molecular weights compared to polymerizations run in methanol.