Enantioselective Visible-Light-Mediated Formation of 3-Cyclopropylquinolones by Triplet-Sensitized Deracemization.

3-Allyl-substituted quinolones undergo a triplet-sensitized di-π-methane rearrangement reaction to the corresponding 3-cyclopropylquinolones upon irradiation with visible light (λ=420 nm). A chiral hydrogen-bonding sensitizer (10 mol %) was shown to promote the reaction enantioselectively (88-96 % yield, 32-55 % ee). Surprisingly, it was found that the enantiodifferentiation does not occur at the state of initial product formation but that it is the result of a deracemization event. The individual parameters that control the distribution of enantiomers in the photostationary state have been identified.

Mechanism and cis/trans Selectivity of Vinylogous Nazarov-type [6π] Photocyclizations †.

Vinylogous Nazarov-type cyclizations yield seven-membered rings from butadienyl vinyl ketones via a photochemical [6π] photocyclization followed by subsequent isomerization steps. The mechanism of this recently developed method was investigated using unrestricted DFT, SF-TDDFT, and CASSCF/NEVPT2 calculations, suggesting three different pathways that lead either to pure trans, pure cis, or mixed cis/trans configured products. Singlet biradicals or zwitterions occur as intermediates. The computational results are supported by deuterium-labeling experiments.

Recent Advances in the Synthesis of Cyclobutanes by Olefin [2 + 2] Photocycloaddition Reactions.

The [2 + 2] photocycloaddition is undisputedly the most important and most frequently used photochemical reaction. In this review, it is attempted to cover all recent aspects of [2 + 2] photocycloaddition chemistry with an emphasis on synthetically relevant, regio-, and stereoselective reactions. The review aims to comprehensively discuss relevant work, which was done in the field in the last 20 years (i.e., from 1995 to 2015). Organization of the data follows a subdivision according to mechanism and substrate classes. Cu(I) and PET (photoinduced electron transfer) catalysis are treated separately in sections 2 and 4 , whereas the vast majority of photocycloaddition reactions which occur by direct excitation or sensitization are divided within section 3 into individual subsections according to the photochemically excited olefin.

Interplay of fast and slow dynamics in rare transition pathways: The disk-to-slab transition in the 2d Ising model.

Rare transitions between long-lived stable states are often analyzed in terms of free energy landscapes computed as functions of a few collective variables. Here, using transitions between geometric phases as example, we demonstrate that the effective dynamics of a system along these variables are an essential ingredient in the description of rare events and that the static perspective provided by the free energy alone may be misleading. In particular, we investigate the disk-to-slab transition in the two-dimensional Ising model starting with a calculation of a two-dimensional free energy landscape and the distribution of committor probabilities. While at first sight it appears that the committor is incompatible with the free energy, they can be reconciled with each other using a two-dimensional Smoluchowski equation that combines the free energy landscape with state dependent diffusion coefficients. These results illustrate that dynamical information is not only required to calculate rate constants but that neglecting dynamics may also lead to an inaccurate understanding of the mechanism of a given process.

Enantioselective Intermolecular [2 + 2] Photocycloaddition Reactions of 2(1H)-Quinolones Induced by Visible Light Irradiation.

In the presence of a chiral thioxanthone catalyst (10 mol %) the title compounds underwent a clean intermolecular [2 + 2] photocycloaddition with electron-deficient olefins at λ = 419 nm. The reactions not only proceeded with excellent regio- and diastereoselectivity but also delivered the respective cyclobutane products with significant enantiomeric excess (up to 95% ee). Key to the success of the reactions is a two-point hydrogen bonding between quinolone and catalyst enabling efficient energy transfer and high enantioface differentiation. Preliminary work indicated that solar irradiation can be used for this process and that the substrate scope can be further expanded to isoquinolones.

Triplet-sensitised di-π-methane rearrangement of N-substituted 2-azabarrelenones.

When irradiated at λ = 366 nm or at λ = 420 nm in the presence of an appropriate sensitiser the title compounds underwent a di-π-methane rearrangement which led to the formation of tricyclic azasemibullvalenones (2a,2a1,2b,4a-tetrahydroazacyclopropa[cd]pentalenones) in yields of 63-87%.

Equilibrium between a Droplet and Surrounding Vapor: A Discussion of Finite Size Effects.

In a theoretical description of homogeneous nucleation one frequently assumes an "equilibrium" coexistence of a liquid droplet with surrounding vapor of a density exceeding that of a saturated vapor at bulk vapor-liquid two-phase coexistence. Thereby one ignores the caveat that in the thermodynamic limit, for which the vapor would be called supersaturated, such states will at best be metastable with finite lifetime, and thus not be well-defined within equilibrium statistical mechanics. In contrast, in a system of finite volume stable equilibrium coexistence of droplet and supersaturated vapor at constant total density is perfectly possible, and numerical analysis of equilibrium free energies of finite systems allows to obtain physically relevant results. In particular, such an analysis can be used to derive the dependence of the droplet surface tension γ( R) on the droplet radius R by computer simulations. Unfortunately, however, the precision of the results produced by this approach turns out to be seriously affected by a hitherto unexplained spurious dependence of γ( R) on the total volume V of the simulation box. These finite size effects are studied here for the standard Ising/lattice gas model in d = 2 dimensions and an Ising model on the face-centered cubic lattice with 3-spin interaction, lacking symmetry between vapor and liquid phases. There also the analogous case of bubbles surrounded by undersaturated liquid is treated. It is argued that (at least a large part of) the finite size effects result from the translation entropy of the droplet or bubble in the system. This effect has been shown earlier to occur also for planar interfaces for simulations in the slab geometry. Consequences for the estimation of the Tolman length are briefly discussed. In particular, we find clear evidence that in d = 2 the leading correction of the curvature-dependent interface tension is a logarithmic term, compatible with theoretical expectations, and we show that then the standard Tolman-style analysis is inapplicable.

Modulation of remifentanil-induced postinfusion hyperalgesia by propofol.

BACKGROUND: Experimental and clinical studies suggest that brief opioid exposure can enhance pain sensitivity. During anesthesia, however, opioids are commonly administered in combination with either IV or inhaled hypnotic drugs. In this investigation we sought to determine the analgesic and antihyperalgesic properties of propofol in subhypnotic concentrations on remifentanil-induced postinfusion hypersensitivity in an experimental human pain model. METHODS: Fifteen healthy volunteers were included in this randomized, double-blind, and placebo-controlled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (41.7 +/- 14.3 mA) induced spontaneous acute pain (numerical rating scale = 6 of 10) and stable areas of hyperalgesia. Pain intensities and areas of hyperalgesia were assessed before, during and after a 30 min target-controlled infusion of propofol (1.5 microg/mL) and remifentanil (0.05 microg x kg(-1) x min(-1)), either alone or in combination (propofol 1.5 microg/mL with remifentanil 0.025 or 0.05 microg x kg(-1) x min(-1)). RESULTS: During infusion, propofol significantly reduced the electrically evoked pain to 72% +/- 21% of control. Subhypnotic concentrations of propofol did not lead to any hyperalgesic effects. Coadministration of remifentanil led to synergistic analgesic effects (to 62% +/- 26% and 58% +/- 25% of control, for 0.025 or 0.05 microg x kg(-1) x min(-1), respectively), but upon withdrawal, pain and hyperalgesia increased above control level. CONCLUSIONS: The results suggest clinically relevant interactions of propofol and remifentanil in humans, since propofol led to a delay and a weakening of remifentanil-induced postinfusion anti-analgesia in humans. Nevertheless, pronociceptive effects were not completely antagonized by propofol, which may account for the increased demand for analgesics after remifentanil-based anesthesia in clinical practice.

Activation of naloxone-sensitive and -insensitive inhibitory systems in a human pain model.

UNLABELLED: We investigated naloxone effects in a model of electrically induced pain and hyperalgesia. In a double-blind, placebo-controlled, cross-over study, 15 volunteers underwent four 150-minute sessions of high-current-density electrical stimulation of their forearms. After 60 minutes, naloxone or placebo was given intravenously (increasing plasma concentrations of 0.1, 1, and 10 ng/mL; 30 minutes each) in 3 of the 4 sessions. Pain ratings and areas of mechanical hyperalgesia were assessed at regular intervals during all sessions. The low doses of naloxone did not cause any significant change of pain rating of areas of hyperalgesia. In terms of intrasession effects, pain ratings and areas of hyperalgesia significantly decreased during the sessions to 62% (pain rating), 70% (area of punctuate hyperalgesia), and 82% (area of allodynia) of the initial values. Naloxone (10 ng/ml) reversed these decreases. In terms of between-session effects, the time course of pain ratings remained constant from session to session. In contrast, the areas of punctate hyperalgesia successively decreased to 60% of initial value at the fourth repetition. The session effect was not reversed by naloxone. High-current-density electrical stimulation provokes central sensitization, but in addition inhibitory systems are activated that are only partly naloxone-sensitive. PERSPECTIVE: Endogenous inhibitory systems are of major importance for clinical pain conditions, but are not reflected in traditional human pain models. Here we show activation of a naloxone-sensitive short-term and a naloxone-insensitive long-term inhibitory system in a new model of electrically induced pain and hyperalgesia.

Wang-Landau sampling with self-adaptive range.

We report a self-adapting version of the Wang-Landau algorithm that is ideally suited for application to systems with a complicated structure of the density of states. Applications include determination of two-dimensional densities of states and high-precision numerical integration of sharply peaked functions on multidimensional integration domains.

Frictional dynamics of stiff monolayers: from nucleation dynamics to thermal sliding.

The inherently nonlinear dynamics of two surfaces as they are driven past each other, a phenomenon known as dry friction, has yet to be fully understood on an atomistic level. New experiments on colloidal monolayers forced over laser-generated substrates now offer the opportunity to investigate friction with single-particle resolution. Here, we use analytical theory and computer simulations to study the effect of thermal fluctuations on the stick-slip mechanism characteristic for the frictional response of a stiff colloidal monolayer on a commensurate substrate. By performing a harmonic expansion of the energy and employing elementary statistical mechanics, we map the motion of the monolayer onto a simple differential equation. Analytical expressions derived from our approach predict a transition from nucleation dynamics, where the monolayer moves in a sequence of activated hops over energy barriers, to "thermal sliding", in which the effective substrate barrier opposing the motion of the monolayer disappears due to thermal fluctuations, leading to continuous, uninterrupted sliding motion. Furthermore, we find that the average velocity of the monolayer for large driving forces obeys a simple scaling behavior that is consistent with the existence of a static friction. For small forces, however, nucleation provides a mode of motion that leads to a small but non-vanishing mobility of the monolayer. Data obtained from simulations confirm this picture and agree quantitatively with our analytical formulae. The theory developed here holds under general conditions for sufficiently strong inter-particle repulsions and it yields specific predictions that can be tested in experiments.

Interaction of fentanyl and buprenorphine in an experimental model of pain and central sensitization in human volunteers.

OBJECTIVES: : There is controversy about combining opioids with different receptor affinities. We assessed the analgesic and antihyperalgesic effects of the µ-agonist fentanyl and the partial µ-agonist/κ-antagonist buprenorphine in a human pain model, when given alone or in combination. METHODS: : Fifteen healthy male volunteers (22 to 35 y) were included in this randomized, double-blind, placebo-controlled, cross-over study. Transcutaneous electrical stimulation induced spontaneous acute pain and stable areas of secondary hyperalgesia. Pain intensities, measured on a numeric rating scale from 0 to 10, and the size of the hyperalgesic areas were assessed before, during, and after an intravenous infusion of 1.5 µg/kg fentanyl, 1.5 µg/kg buprenorphine, a combination of 0.75 µg/kg fentanyl and buprenorphine each, or saline 0.9%. Maximum effects of the treatments were compared by repeated measurement analysis of variance, and pharmacodynamic interaction models were fitted to the data. RESULTS: : Starting from a baseline value of numeric rating scale=6, the maximum reduction of pain intensity after correction for placebo effects was 43.9 ± 22.2% after fentanyl, 35.0 ± 23.0% after buprenorphine, and 39.4 ± 20.8% after the combination (mean ± SD, P=0.24). The maximum reduction of the hyperalgesic area was 38.3 ± 39.0% for fentanyl, 34.4 ± 32.7% for buprenorphine, and 30.0 ± 53.8% for the combination (mean ± SD, P=0.82). The time courses were best described by pharmacodynamic models assuming an additive interaction. DISCUSSION: : For the doses administered in this study, buprenorphine and fentanyl showed an additive interaction.

Supra-additive effects of tramadol and acetaminophen in a human pain model.

The combination of analgesic drugs with different pharmacological properties may show better efficacy with less side effects. Aim of this study was to examine the analgesic and antihyperalgesic properties of the weak opioid tramadol and the non-opioid acetaminophen, alone as well as in combination, in an experimental pain model in humans. After approval of the local Ethics Committee, 17 healthy volunteers were enrolled in this double-blind and placebo-controlled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (29.6+/-16.2 mA) induced spontaneous acute pain (NRS=6 of 10) and distinct areas of hyperalgesia for painful mechanical stimuli (pinprick-hyperalgesia). Pain intensities as well as the extent of the areas of hyperalgesia were assessed before, during and 150 min after a 15 min lasting intravenous infusion of acetaminophen (650 mg), tramadol (75 mg), a combination of both (325 mg acetaminophen and 37.5mg tramadol), or saline 0.9%. Tramadol led to a maximum pain reduction of 11.7+/-4.2% with negligible antihyperalgesic properties. In contrast, acetaminophen led to a similar pain reduction (9.8+/-4.4%), but a sustained antihyperalgesic effect (34.5+/-14.0% reduction of hyperalgesic area). The combination of both analgesics at half doses led to a supra-additive pain reduction of 15.2+/-5.7% and an enhanced antihyperalgesic effect (41.1+/-14.3% reduction of hyperalgesic areas) as compared to single administration of acetaminophen. Our study provides first results on interactions of tramadol and acetaminophen on experimental pain and hyperalgesia in humans. Pharmacodynamic modeling combined with the isobolographic technique showed supra-additive effects of the combination of acetaminophen and tramadol concerning both, analgesia and antihyperalgesia. The results might act as a rationale for combining both analgesics.

Modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by parecoxib in humans.

BACKGROUND: Numerous experimental and clinical studies suggest that brief opioid exposure can enhance pain sensitivity. It is suggested that spinal cyclooxygenase activity may contribute to the development and expression of opioid tolerance. The aim of the investigation was to determine analgesic and antihyperalgesic properties of the cyclooxygenase-2 inhibitor parecoxib on remifentanil-induced hypersensitivity in humans. METHODS: Fifteen healthy male volunteers were enrolled in this randomized, double-blind, placebo-controlled study in a crossover design. Transcutaneous electrical stimulation at high current densities was used to induce spontaneous acute pain (numeric rating scale 6 of 10) and stable areas of pinprick hyperalgesia. Pain intensities and areas of hyperalgesia were assessed before, during, and after a 30-min intravenous infusion of remifentanil (0.1 microg x kg x min) or placebo (saline). Parecoxib (40 mg) was administered intravenously either with onset of electrical stimulation (preventive) or in parallel to the remifentanil infusion. RESULTS: Remifentanil reduced pain and mechanical hyperalgesia during the infusion, but upon withdrawal, pain and hyperalgesia increased significantly above control level. Preventive administration of parecoxib led to an amplification of remifentanil-induced antinociceptive effects during the infusion (71.3 +/- 7 vs. 46.4 +/- 17% of control) and significantly diminished the hyperalgesic response after withdrawal. In contrast, parallel administration of parecoxib did not show any modulatory effects on remifentanil-induced hyperalgesia. CONCLUSION: The results confirm clinically relevant interaction of mu opioids and prostaglandins in humans. Adequate timing seems to be of particular importance for the antihyperalgesic effect of cyclooxygenase-2 inhibitors.