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Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aims: Alzheimer's disease (AD) is a devastating dementia characterized by extracellular amyloid‐β (Aβ) protein aggregates and intracellular tau protein deposition. Clinically available drugs mainly target acetylcholinesterase (AChE) and indirectly sustain cholinergic neuronal tonus. Butyrylcholinesterase (BChE) also controls acetylcholine (ACh) turnover and is involved in the formation of Aß aggregates and senile plaques. UW‐MD‐95 is a novel carbamate‐based compound acting as a potent pseudo‐irreversible BChE inhibitor, with high selectivity versus AChE, and showing promising protective potentials in AD. Methods: We characterized the neuroprotective activity of UW‐MD‐95 in mice treated intracerebroventricularly with oligomerized Aβ25‐35 peptide using behavioral, biochemical, and immunohistochemical approaches. Results: When injected acutely 30 min before the behavioral tests (spontaneous alternation in the Y‐maze, object recognition, or passive avoidance), UW‐MD‐95 (0.3‐3 mg/kg) showed anti‐amnesic effects in Aβ25‐35‐treated mice. When injected once a day over 7 days, it prevented Aβ25‐35‐induced memory deficits. This effect was lost in BChE knockout mice. Moreover, the compound prevented Aβ25‐35‐induced oxidative stress (assessed by lipid peroxidation or cytochrome c release), neuroinflammation (IL‐6 and TNFα levels or GFAP and IBA1 immunoreactivity) in the hippocampus and cortex, and apoptosis (Bax level). Moreover, UW‐MD‐95 significantly reduced the increase in soluble Aβ1‐42 level in the hippocampus induced by Aβ25‐35. Conclusion: UW‐MD‐95 appeared as a potent neuroprotective compound in the Aβ25‐35 model of AD, with potentially an impact on Aβ1‐42 accumulation that could suggest a novel mechanism of neuroprotection. [ABSTRACT FROM AUTHOR]

β2‐adrenergic receptor (β2‐AR) agonists are used for the treatment of asthma and chronic obstructive pulmonary disease, but also play a role in other complex disorders including cancer, diabetes and heart diseases. As the cellular and molecular mechanisms in various cells and tissues of the β2‐AR remain vastly elusive, we developed tools for this investigation with high temporal and spatial resolution. Several photoswitchable β2‐AR agonists with nanomolar activity were synthesized. The most potent agonist for β2‐AR with reasonable switching is a one‐digit nanomolar active, trans‐on arylazopyrazole‐based adrenaline derivative and comprises valuable photopharmacological properties for further biological studies with high structural accordance to the native ligand adrenaline. [ABSTRACT FROM AUTHOR]

To interrogate neural circuits and crack their codes, in vivo brain activity imaging must be combined with spatiotemporally precise stimulation in three dimensions using genetic or pharmacological specificity. This challenge requires deep penetration and focusing as provided by infrared light and multiphoton excitation, and has promoted two‐photon photopharmacology and optogenetics. However, three‐photon brain stimulation in vivo remains to be demonstrated. We report the regulation of neuronal activity in zebrafish larvae by three‐photon excitation of a photoswitchable muscarinic agonist at 50 pM, a billion‐fold lower concentration than used for uncaging, and with mid‐infrared light of 1560 nm, the longest reported photoswitch wavelength. Robust, physiologically relevant photoresponses allow modulating brain activity in wild‐type animals with spatiotemporal and pharmacological precision. Computational calculations predict that azobenzene‐based ligands have high three‐photon absorption cross‐section and can be used directly with pulsed infrared light. The expansion of three‐photon pharmacology will deeply impact basic neurobiology and neuromodulation phototherapies. [ABSTRACT FROM AUTHOR]

Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The cannabinoid 2 receptor (CB2R) has high therapeutic potential for multiple pathogenic processes, such as neuroinflammation. Pathway‐selective ligands are needed to overcome the lack of clinical success and to elucidate correlations between pathways and their respective therapeutic effects. Herein, we report the design and synthesis of a photoswitchable scaffold based on the privileged structure of benzimidazole and its application as a functionally selective CB2R "efficacy‐switch". Benzimidazole azo‐arenes offer huge potential for the broad extension of photopharmacology to a wide range of optically addressable biological targets. We used this scaffold to develop compound 10 d, a "trans‐on" agonist, which serves as a molecular probe to study the β‐arrestin2 (βarr2) pathway at CB2R. βΑrr2 bias was observed in CB2R internalization and βarr2 recruitment, while no activation occurred when looking at Gα16 or mini‐Gαi. Overall, compound 10 d is the first light‐dependent functionally selective agonist to investigate the complex mechanisms of CB2R‐βarr2 dependent endocytosis. [ABSTRACT FROM AUTHOR]

Highly cross‐linked polyethylene (HXLPE) for total hip arthroplasty was developed to improve wear resistance in vivo and associated complications in comparison to ultrahigh molecular weight polyethylene. This material typically goes through various free‐radical stabilization techniques by remelting, single‐annealing, or sequentially annealing the polyethylene to improve in vivo oxidation and wear properties. The purpose of this study is to determine if there is evidence of subsurface microhardness changes in retrieved HXLPE liner at the rim and articular subsurface after extended in vivo time that could be associated with oxidation and its effects on mechanical properties and implant integrity. Retrieved HXLPE liners were chosen based on peak subsurface Fourier transform infrared spectroscopy oxidation values. Each was mechanically tested for subsurface microhardness at both the rim and articular surface using a validated microindentation technique. Rim testing demonstrated a decrease in mechanical integrity that corresponded to higher subsurface oxidation values regardless of the free‐radical stabilization technique. At the articular surface, a decrease in mechanical integrity was observed near the surface corresponding to peak oxidation and Vicker's hardness, which decreased with increasing depths. This was found in all groups, with the exception of the single‐annealed liners, which demonstrated decreased mechanical integrity trends at greater depths between 1.0 and 2.0 mm. Our results suggest that subsurface mechanical properties do change in vivo for certain implants. Though it is likely that the mechanical failures are multifactorial, we have shown that mechanical property degradation of HXLPE liners does occur with long‐term in vivo exposure and should be considered a possible risk factor. [ABSTRACT FROM AUTHOR]

Flavonoids are polyphenolic natural products and have shown significant potential as disease‐modifying agents against neurodegenerative disorders like Alzheimer's disease (AD), with activities even in vivo. Hybridization of the natural products taxifolin and silibinin with cinnamic acid led to an overadditive effect of these compounds in several phenotypic screening assays related to neurodegeneration and AD. Therefore, we have exchanged the flavonoid part of the hybrids with different flavonoids, which show higher efficacy than taxifolin or silibinin, to improve the activity of the respective hybrids. Chemical connection between the flavonoid and cinnamic acid was realized by an amide instead of a labile ester bond to improve stability towards hydrolysis. To investigate the influence of a double bond at the C‐ring of the flavonoid, the dehydro analogues of the respective hybrids were also synthesized. All compounds obtained show neuroprotection against oxytosis, ferroptosis and ATP‐depletion, respectively, in the murine hippocampal cell line HT22. Interestingly, the taxifolin and the quercetin derivatives are the most active compounds, whereby the quercetin derivate shows even more pronounced activity than the taxifolin one in all assays applied. As aimed for, no hydrolysis product was found in cellular uptake experiments after 4 h whereas different metabolites were detected. Furthermore, the quercetin‐cinnamic acid amide showed pronounced activity in an in vivo AD mouse model at a remarkably low dose of 0.3 mg/kg. [ABSTRACT FROM AUTHOR]

Classical psychedelics are a group of hallucinogens which trigger non‐ordinary states of consciousness through activation of the 5‐HT2A receptor (5‐HT2AR) in the brain. However, the exact mechanism of how 5‐HT2AR agonism alters perception remains elusive. When studying receptor signaling, tools which work at the same spatiotemporal resolution as the receptor are exceptionally useful. To create such a tool, we designed a set of photoswitchable ligands based on the classical psychedelic N,N‐dimethyltryptamine (DMT). By incorporation of the DMT‐indole ring into the photoswitchable system, we obtained red‐shifted ligands which can be operated by visible light. Among these azo‐DMTs, compound 2 h ("Photo‐DMT") stands out as its cis isomer exhibits DMT like activity while the trans isomer acts as weak partial agonist. Such a cis‐on "efficacy switch" substantially expands the pharmacological toolbox to investigate the complex mechanisms of 5‐HT2AR signaling. [ABSTRACT FROM AUTHOR]

Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Recently described rhizolutin and collinolactone isolated from Streptomyces Gö 40/10 share the same novel carbon scaffold. Analyses by NMR and X‐Ray crystallography verify the structure of collinolactone and propose a revision of rhizolutin's stereochemistry. Isotope‐labeled precursor feeding shows that collinolactone is biosynthesized via type I polyketide synthase with Baeyer–Villiger oxidation. CRISPR‐based genetic strategies led to the identification of the biosynthetic gene cluster and a high‐production strain. Chemical semisyntheses yielded collinolactone analogues with inhibitory effects on L929 cell line. Fluorescence microscopy revealed that only particular analogues induce monopolar spindles impairing cell division in mitosis. Inspired by the Alzheimer‐protective activity of rhizolutin, we investigated the neuroprotective effects of collinolactone and its analogues on glutamate‐sensitive cells (HT22) and indeed, natural collinolactone displays distinct neuroprotection from intracellular oxidative stress. [ABSTRACT FROM AUTHOR]

Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Many (poly‐)phenolic natural products, for example, curcumin and taxifolin, have been studied for their activity against specific hallmarks of neurodegeneration, such as amyloid‐β 42 (Aβ42) aggregation and neuroinflammation. Due to their drawbacks, arising from poor pharmacokinetics, rapid metabolism, and even instability in aqueous medium, the biological activity of azobenzene compounds carrying a pharmacophoric catechol group, which have been designed as bioisoteres of curcumin has been examined. Molecular simulations reveal the ability of these compounds to form a hydrophobic cluster with Aβ42, which adopts different folds, affecting the propensity to populate fibril‐like conformations. Furthermore, the curcumin bioisosteres exceeded the parent compound in activity against Aβ42 aggregation inhibition, glutamate‐induced intracellular oxidative stress in HT22 cells, and neuroinflammation in microglial BV‐2 cells. The most active compound prevented apoptosis of HT22 cells at a concentration of 2.5 μm (83 % cell survival), whereas curcumin only showed very low protection at 10 μm (21 % cell survival). [ABSTRACT FROM AUTHOR]

Considerable effort has previously been invested in a light‐controlled inhibition of the enzyme acetylcholinesterase (AChE). We found that a novel azobenzene‐based bistacrine AChE inhibitor switched faster than the known dithienylethene based bistacrine and inverted the photo‐controlled interactions of the photoisomers compared to its dithienylethene congener. Furthermore, we have optimized a previously described light‐controlled tacrine‐based AChE inhibitor. Isomerization upon irradiation with UV light of the novel inhibitor was observed in aqueous medium and showed no fatigue over several cycles. The cis‐enriched form showed an 8.4‐fold higher inhibition of hAChE compared with its trans‐enriched form and was about 30‐fold more active than the reference compound tacrine with a single‐digit nanomolar inhibition. We went beyond proof‐of‐concept to discover photoswitchable AChE inhibitors with pharmacologically desirable nanomolar inhibition, "cis‐on" effect, and pronounces differences between the photoisomers. [ABSTRACT FROM AUTHOR]

Key points: Extreme aviation is accompanied by ever‐present risks of hypobaric hypoxia and decompression sickness. Neuroprotection against those hazards is conferred through fractional inspired oxygen (FI,O2) concentrations of 60–100% (hyperoxia).Hyperoxia reduces global cerebral perfusion (gCBF), increases reactive oxygen species within the brain and leads to cell death within the hippocampus. However, an understanding of hyperoxia's effect on cortical activity and concomitant levels of cognitive performance is lacking. This limits our understanding of whether hyperoxia could lower the brain's threshold of tolerance to physiological stressors inherent to extreme aviation, such as high gravitational forces.This study aimed to quantify the impact of hyperoxia upon global cerebral perfusion (gCBF), cognitive performance and cortical electroencephalography (EEG).Hyperoxia evoked a rapid reduction in gCBF, yet cognitive performance and vigilance were enhanced. EEG measurements revealed enhanced alpha power, suggesting less desynchrony, within the cortical temporal regions.Collectively, this work suggests hyperoxia‐induced brain hypoperfusion is accompanied by enhanced cognitive processing and cortical arousal. Extreme aviators continually inspire hyperoxic gas to mitigate risk of hypoxia and decompression injury. This neuroprotection carries a physiological cost: reduced cerebral perfusion (CBF). As reduced CBF may increase vulnerability to ever‐present physiological challenges during extreme aviation, we defined the magnitude and duration of hyperoxia‐induced changes in CBF, cortical electrical activity and cognition in 30 healthy males and females. Magnetic resonance imaging with pulsed arterial spin labelling provided serial measurements of global CBF (gCBF), first during exposure to 21% inspired oxygen (FI,O2) followed by a 30‐min exposure to 100% FI,O2. High‐density EEG facilitated characterization of cortical activity during assessment of cognitive performance, also measured during exposure to 21% and 100% FI,O2. Acid‐base physiology was measured with arterial blood gases. We found that exposure to 100% FI,O2 reduced gCBF to 63% of baseline values across all participants. Cognitive performance testing at 21% FI,O2 was accompanied by increased theta and beta power with decreased alpha power across multiple cortical areas. During cognitive testing at 100% FI,O2, alpha activity was less desynchronized within the temporal regions than at 21% FI,O2. The collective hyperoxia‐induced changes in gCBF, cognitive performance and EEG were similar across observed partial pressures of arterial oxygen (PaO2), which ranged between 276–548 mmHg, and partial pressures of arterial carbon dioxide (PaCO2), which ranged between 34–50 mmHg. Sex did not influence gCBF response to 100% FI,O2. Our findings suggest hyperoxia‐induced reductions in gCBF evoke enhanced levels of cortical arousal and cognitive processing, similar to those occurring during a perceived threat. Key points: Extreme aviation is accompanied by ever‐present risks of hypobaric hypoxia and decompression sickness. Neuroprotection against those hazards is conferred through fractional inspired oxygen (FI,O2) concentrations of 60–100% (hyperoxia).Hyperoxia reduces global cerebral perfusion (gCBF), increases reactive oxygen species within the brain and leads to cell death within the hippocampus. However, an understanding of hyperoxia's effect on cortical activity and concomitant levels of cognitive performance is lacking. This limits our understanding of whether hyperoxia could lower the brain's threshold of tolerance to physiological stressors inherent to extreme aviation, such as high gravitational forces.This study aimed to quantify the impact of hyperoxia upon global cerebral perfusion (gCBF), cognitive performance and cortical electroencephalography (EEG).Hyperoxia evoked a rapid reduction in gCBF, yet cognitive performance and vigilance were enhanced. EEG measurements revealed enhanced alpha power, suggesting less desynchrony, within the cortical temporal regions.Collectively, this work suggests hyperoxia‐induced brain hypoperfusion is accompanied by enhanced cognitive processing and cortical arousal. [ABSTRACT FROM AUTHOR]

Alzheimer′s disease (AD) is a neurological disorder with still no preventive or curative treatment. Flavonoids are phytochemicals with potential therapeutic value. Previous studies described the flavanone sterubin isolated from the Californian plant Eriodictyon californicum as a potent neuroprotectant in several in vitro assays. Herein, the resolution of synthetic racemic sterubin (1) into its two enantiomers, (R)‐1 and (S)‐1, is described, which has been performed on a chiral chromatographic phase, and their stereochemical assignment online by HPLC‐ECD coupling. (R)‐1 and (S)‐1 showed comparable neuroprotection in vitro with no significant differences. While the pure stereoisomers were configurationally stable in methanol, fast racemization was observed in the presence of culture medium. We also established the occurrence of extracted sterubin as its pure (S)‐enantiomer. Moreover, the activity of sterubin (1) was investigated for the first time in vivo, in an AD mouse model. Sterubin (1) showed a significant positive impact on short‐ and long‐term memory at low dosages. [ABSTRACT FROM AUTHOR]

Opioid receptors (ORs) are classified among the oldest and best investigated drug targets due to their fundamental role in the treatment of pain and related disorders. ORs are divided in three conventional subtypes (μ, κ, δ) and the non‐classical nocicepetin receptor. All ORs are family A G protein‐coupled receptors (GPCRs), and are located on the cell surface. Modern biophysical methods use light to investigate physiological processes at organismal, cellular and subcellular level. Many of these methods rely on fluorescent ligands, thus highlighting their importance. This review addresses the advancements in the development of opioid fluorescent ligands and their use in biological, pharmacological and imaging applications. [ABSTRACT FROM AUTHOR]

μ‐Opioid receptors (μ‐ORs) play a critical role in the modulation of pain and mediate the effects of the most powerful analgesic drugs. Despite extensive efforts, it remains insufficiently understood how μ‐ORs produce specific effects in living cells. We developed new fluorescent ligands based on the μ‐OR antagonist E‐p‐nitrocinnamoylamino‐dihydrocodeinone (CACO), that display high affinity, long residence time and pronounced selectivity. Using these ligands, we achieved single‐molecule imaging of μ‐ORs on the surface of living cells at physiological expression levels. Our results reveal a high heterogeneity in the diffusion of μ‐ORs, with a relevant immobile fraction. Using a pair of fluorescent ligands of different color, we provide evidence that μ‐ORs interact with each other to form short‐lived homodimers on the plasma membrane. This approach provides a new strategy to investigate μ‐OR pharmacology at single‐molecule level. [ABSTRACT FROM AUTHOR]

An efficient and scalable rule‐based syntactic differencing approach is presented. The tool srcDiff is built upon the srcML infrastructure. srcML adds abstract syntactic information into the code via an XML format. A syntactic difference of srcML documents is then taken. During this process, the differences are further refined using a set of rules that model typical editing patterns of source code by developers. Thus, the resulting deltas model edits that are programmer centric versus a purely syntactic tree edit view. Other syntactic differencing approaches focus on obtaining an optimal tree edit distance with the assumption that this will produce an accurate difference. While this may work well for small or simple changes, the differences quickly become unreadable for more complex changes. By contrast, the approach presented here purposely deviates from an optimal tree edit difference in order to create a delta that is both easier to understand and better models changes between the original and modified. To evaluate the approach, a comparison user study against a state‐of‐the‐art syntactic differencing approach and two line‐based differencing tools is conducted as an online within‐participant study with about 70 subjects on 14 sample changes. The results provide support that the rule‐based syntactic differencing produces more accurate and understandable deltas. [ABSTRACT FROM AUTHOR]

Keywords: Funktionell Selektiver Ligand; G-Protein-Gekoppelter Rezeptor; Optische Kontrolle; Photopharmakologie; BenzimidazolePhotopharmacology. Visible‐light photoswitchable benzimidazole azo‐arenes as β‐arrestin2‐biased cannabinoid 2 receptor agonists are reported by Michael Decker et al. in their Research Article (e202306176)...By Sophie A. M. Steinmüller; Julia Fender; Marie H. Deventer; Anna Tutov; Kristina Lorenz; Christophe P. Stove; James N. Hislop and Michael DeckerReported by Author; Author; Author; Author; Author; Author; Author; Author [Extracted from the article]

Keywords: Benzimidazoles; Biased Ligand; G Protein-Coupled Receptor; Optical Control; PhotopharmacologyPhotopharmacology. Visible‐light photoswitchable benzimidazole azo‐ arenes as β‐arrestin2‐biased cannabinoid 2 receptor agonists are reported by Michael Decker et al. in their Research Article (e202306176)...By Sophie A. M. Steinmüller; Julia Fender; Marie H. Deventer; Anna Tutov; Kristina Lorenz; Christophe P. Stove; James N. Hislop and Michael DeckerReported by Author; Author; Author; Author; Author; Author; Author; Author [Extracted from the article]

Dehydromenthofurolactone (tonkafuranone) and other bicyclic lactones are common flavour compounds and can be found in a variety of plants. Herein, we present an improved synthesis of the natural product and a series of close analogues, in combination with efficient purification methods for simple preparation from cheap and easily accessible chemicals. A two‐step, one‐pot, reaction procedure, consisting of an aldol condensation step with concomitant lactonization, yields simplified analogues of the natural parent compound (R)‐tonkafuranone and its likewise natural (S)‐enantiomer, lacking one or two of its methyl groups, respectively. In the case of regioisomeric products, these were resolved by preparative high‐performance liquid chromatography, which, in the case of chiral, yet racemic products, was followed by preparative enantio‐resolution on a chiral phase, permitting the isolation of all four pure isomers from one synthetic step. Using the stereo‐analytical method developed, the enantiomeric purity of natural tonkafuranone occurring in Bursera graveolens was analysed and found to be '100:0' in favour of the S‐enantiomer. The chiral, enantiomerically pure products were configurationally assigned by co‐elution, semi‐synthesis, and/or chiroptical methods. With the pure isomers obtained, specific cytotoxicities were tested in two cell lines as a measure for their reactivities towards cellular nucleophiles. Although the synthesized compounds differed in their cytotoxic potential in V79 cells, they exhibited a much smaller cytotoxic potential than the mutagenic α,β,γ,δ‐unsaturated lactone patulin. No toxicity towards murine hippocampal HT‐22 cells was observed at 50 μM. Thus, the molecular mechanism contributing to the high reactivity of patulin towards nucleophiles may not apply for tonkafuranone and structurally related compounds. [ABSTRACT FROM AUTHOR]

Byzantine archeology embraces the study of material culture in the Byzantine Empire (the continuation of the Roman Empire in the Eastern Mediterranean from the 4th through 15th centuries C.E.). This review examines current trends in Byzantine archeology, among which one finds new local and regional studies, and a decided move away from archeological excavation to archeological survey and other forms of noninvasive investigation. There is still a strong orientation among scholars engaged with Byzantine archeology to explain the nature and mechanisms of change around the period of transition from antiquity to the medieval period. New theories and methodologies, often slow to be adopted by Byzantinists, are now routinely applied in many areas of Byzantine archeology. More recently, the archeological sciences, including studies involving climate change and the diet, have become more prominent in the field. Finally, in order to thrive, Byzantine archeology is a scholarly pursuit in need of institutional support and a defined and effective academic network. [ABSTRACT FROM AUTHOR]

Since the 19th century, scholars have examined the end of the Classical world and the beginning of the medieval world, or '"Late Antiquity" in the centuries from 300-900 C.E. through the lens of environmental history. Environmental determinism, based on the use of history by colonial historians, employed elements from geography, climate, and landscape studies to explain the fall of the Roman Empire, the rise of Islam in Arabia, and the destruction of the formerly fertile lands of the Roman Empire by marauding Bedouin. Recent studies stress the importance of intensive regional study while reversing the view of general environmental catastrophe and economic decline once thought to accompany the Arab conquests of the late antique Levant. [ABSTRACT FROM AUTHOR]

A growing body of scholarly literature on climate change from various disciplines has allowed historians to construct past possible climates and environments, as well as query climatological data in light of historical sources. This article presents important phenomena and environmental studies in light of the history of Late Antiquity and the 'Dark Ages' (fourth through ninth centuries C.E.) in the Roman and post-Roman Mediterranean. [ABSTRACT FROM AUTHOR]

The investigation of the mode and time course of the activation of G-protein-coupled receptors (GPCRs), in particular muscarinic acetylcholine (mACh or M) receptors, is still in its infancy despite the tremendous therapeutic relevance of M receptors and GPCRs in general. We herein made use of a dualsteric ligand that can concomitantly interact with the orthosteric, that is, the neurotransmitter, binding site and an allosteric one. We synthetically incorporated a photoswitchable (photochromic) azobenzene moiety. We characterized the photophysical properties of this ligand called BQCAAI and investigated its applicability as a pharmacological tool compound with a set of FRET techniques at the M1 receptor. BQCAAI proved to be an unprecedented molecular tool; it is the first photoswitchable dualsteric ligand, and its activity can be regulated by light. We also applied BQCCAI to investigate the time course of several receptor activation processes. [ABSTRACT FROM AUTHOR]

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Background: ABT-126 is a novel, safe, and well-tolerated α7 nicotinic receptor agonist in a Phase 2 Alzheimer's disease study. We tested the antidyskinetic effect of ABT-126 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated squirrel monkeys with moderate and more severe nigrostriatal damage.Methods: Monkeys (n = 21, set 1) were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1-2×. When parkinsonian, they were gavaged with levodopa (10 mg/kg)/carbidopa (2.5 mg/kg) twice daily and dyskinesias rated. They were then given nicotine in drinking water (n = 5), or treated with vehicle (n = 6) or ABT-126 (n = 10) twice daily orally 30 min before levodopa. Set 1 was then re-lesioned 1 to 2 times for a total of 3 to 4 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injections. The antidyskinetic effect of ABT-126, nicotine, and the β2* nicotinic receptor agonist ABT-894 was re-assessed. Another group of monkeys (n = 23, set 2) were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine only 1× to 2×. They were treated with levodopa/carbidopa, administered the α7 agonist ABT-107 (n = 6), ABT-894 (n = 6), nicotine (n = 5), or vehicle (n = 6) and dyskinesias evaluated. All monkeys were euthanized and the dopamine transporter measured.Results: With moderate nigrostriatal damage (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1×-2×), ABT-126 dose-dependently decreased dyskinesias (∼60%), with similar results seen with ABT-894 (∼60%) or nicotine (∼60%). With more severe damage (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 3-4×), ABT-126 and nicotine reduced dyskinesias, but ABT-894 did not. The dopamine transporter was 41% and 8.9% of control, with moderate and severe nigrostriatal damage, respectively. No drug modified parkinsonism.Conclusion: The novel α7 nicotinic receptor drug ABT-126 reduced dyskinesias in monkeys with both moderate and severe nigrostriatal damage. ABT-126 may be useful to reduce dyskinesias in both early- and later-stage Parkinson's disease. [ABSTRACT FROM AUTHOR]

ABSTRACT Levodopa-induced dyskinesias (LIDs) are a serious complication of levodopa therapy for Parkinson's disease for which there is little treatment. Accumulating evidence shows that nicotinic acetylcholine receptor (nAChR) drugs decrease LIDs in parkinsonian animals. Here, we examined the effect of two β2 nAChR agonists, ABT-089 and ABT-894, that previously were approved for phase 2 clinical trials for other indications. Two sets of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys were administered levodopa/carbidopa (10 mg/kg and 2.5 mg/kg, respectively) twice daily 5 days a week until they were stably dyskinetic. Each set had a vehicle-treated group, an nAChR agonist-treated group, and a nicotine-treated group as a positive control. Set A monkeys had previously received other nAChR drugs (nAChR drug-primed), whereas Set B monkeys were initially nAChR drug-naive. Both sets were administered the partial agonist ABT-089 (range, 0.01-1.0 mg/kg) orally 5 days a week twice daily 30 minutes before levodopa with each dose given for 1 to 5 weeks. ABT-089 decreased LIDs by 30% to 50% compared with vehicle-treated monkeys. Nicotine reduced LIDs by 70% in a parallel group. After 4 weeks of washout, the effect of the full agonist ABT-894 (range, 0.0001-0.10 mg/kg) was assessed on LIDs in Set A and Set B. ABT-894 reduced LIDs by 70%, similar to nicotine. Both drugs acted equally well at α4β2* and α6β2* nAChRs; however, ABT-089 was 30 to 60 times less potent than ABT-894. Tolerance did not develop for the time periods tested (range, 3-4 months). The nAChR drugs did not worsen parkinsonism or cognitive ability. Emesis, a common problem with nAChR drugs, was not observed. ABT-894 and ABT-089 appear to be good candidate nAChR drugs for the management of LIDs in Parkinson's disease. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

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Purpose Mutations in the voltage-gated sodium channel (VGSC) gene SCN1A are responsible for a number of epilepsy disorders, including genetic epilepsy with febrile seizures plus ( GEFS+) and Dravet syndrome. In addition to seizures, patients with SCN1A mutations often experience sleep abnormalities, suggesting that SCN1A may also play a role in the neuronal pathways involved in the regulation of sleep. However, to date, a role for SCN1A in the regulation of sleep architecture has not been directly examined. To fill this gap, we tested the hypothesis that SCN1A contributes to the regulation of sleep architecture, and by extension, that SCN1A dysfunction contributes to the sleep abnormalities observed in patients with SCN1A mutations. Methods Using immunohistochemistry we first examined the expression of mouse Scn1a in regions of the mouse brain that are known to be involved in seizure generation and sleep regulation. Next, we performed detailed analysis of sleep and wake electroencephalography ( EEG) patterns during 48 continuous hours of baseline recordings in a knock-in mouse line that expresses the human SCN1A GEFS+ mutation R1648H ( RH mutants). We also characterized the sleep-wake pattern following 6 h of sleep deprivation. Key Findings Immunohistochemistry revealed broad expression of Scn1a in the neocortex, hippocampus, hypothalamus, thalamic reticular nuclei, dorsal raphe nuclei, pedunculopontine, and laterodorsal tegmental nuclei. Co-localization between Scn1a immunoreactivity and critical cell types within these regions was also observed. EEG analysis under baseline conditions revealed increased wakefulness and reduced non-rapid eye movement ( NREM) and rapid eye movement ( REM) sleep amounts during the dark phase in the RH mutants, suggesting a sleep deficit. Nevertheless, the mutants exhibited levels of NREM and REM sleep that were generally similar to wild-type littermates during the recovery period following 6 h of sleep deprivation. Significance These results establish a direct role for SCN1A in the regulation of sleep and suggest that patients with SCN1A mutations may experience chronic alterations in sleep, potentially leading to negative outcomes over time. In addition, the expression of Scn1a in specific cell types/brain regions that are known to play critical roles in seizure generation and sleep now provides a mechanistic basis for the clinical features (seizures and sleep abnormalities) associated with human SCN1A mutations. [ABSTRACT FROM AUTHOR]

The effect of NO-metoprolol, that is, 3-nitrooxypivaloyl metoprolol-amide, a novel NO-releasing derivative of the β1-blocking drug metoprolol was investigated in A.CA/SnJ mice infected with coxsackievirus B3 (CVB3) and compared to metoprolol and placebo. Daily treatment of mice with the respective drug started immediately (experiment A) or 3 days after virus infection (experiment B) and was continued until day 13 post-infection (p.i.). Two doses of NO-metoprolol were administered. Body mass differences, viral load, and histopathological signs of myocarditis were compared between the several groups. As a result, NO-metoprolol diminished significantly the body weight loss, the viral load and the histopathology, whereas metoprolol treatment led solely to a significant attenuation of myocardial damage. In experiment A, low dose NO-metoprolol decreased significantly enteroviral copy numbers. Both doses of NO-metoprolol had a significant effect on reduction of myocardial infiltrates and fibrosis. The data suggest that delayed drug administration might more advantageous. Both doses of NO-metoprolol reduced significantly the scores of four tested parameters compared to placebo. Body weight loss, virus titers, plus-strand as well as minus-strand enteroviral RNA levels, infiltration and fibrosis scores were diminished significantly when NO-metoprolol was given 3 days p.i. In addition, a significant difference regarding the enteroviral copy numbers was observed between low dose NO-metoprolol- and metoprolol-treated mice. Treatment with metoprolol reduced insignificantly the viral load and body weight loss (experiment A and B) but led to a significant reduction of myocardial histopathology in experiment A. The results indicate that NO-metoprolol treatment has a greater therapeutic benefit than metoprolol. J. Med. Virol. 82:2043-2052, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The thiazolidinediones (TZDs) or glitazones are pharmaceutical agents that have profound effects on energy expenditure and conservation. They also exert significant anti-inflammatory effects and influence cell proliferation and cell death. The drugs are primarily used in clinical practice in the treatment of patients with type 2 diabetes mellitus, a disorder of insulin resistance that occurs when the pancreatic β-cells are unable to produce adequate amounts of insulin to maintain euglycaemia. Loss of pancreatic β-cell function in type 2 diabetes is progressive and often precedes overt diabetes by 10 years or more, as was shown by the United Kingdom Prospective Diabetes Study. Any therapeutic or preventive approach that would limit or reverse loss of β-cell function in diabetes would have profound effects on the morbidity associated with this widespread disease. Evidence suggesting a potential role of TZDs in preserving β-cell function in type 2 diabetes as well as the ability of these agents to exert anti-inflammatory and proapoptotic anticancer effects, and their ability to promote cellular proliferation in various organs is reviewed. [ABSTRACT FROM AUTHOR]