Design and Synthesis of Achiral and Chiral Imidazodiazepine (IMDZ) GABA(A)R Subtype Selective Ligands for the Treatment of CNS Disorders, as well as Asthma

Gamma-aminobutyric acid type A receptors (GABAAR) are transmembrane pentameric ligand-gated chloride ion channels that respond to GABA, the major inhibitory neurotransmitter in the central nervous systems (CNS). The benzodiazepines (BZDs) bind at the extracellular interface of the α+γ2-subunits of GABAAR. The binding of ligands at different subunits of GABAA receptors specifically at α1-6β2/3 γ2 ion channels, can affect a wide variety of brain functions. The α1-subtype selective ion channels of GABAARs are involved in the sedative, ataxic, amnesic, anticonvulsant and addictive effects, which should be avoided, with the exception of the anticonvulsant effects, when designing ligands for this BZ allosteric modulatory site. The α2/3-containing GABAARs have been implicated by many, in the anxiolytic, anticonvulsant, and antinociceptive activities. At higher doses, muscle relaxation may be mediated by interaction at α3 subtypes. It is known that α5-containing GABAARs are involved in cognition, as well as learning and memory processes. The disruption of GABA activity at α5 subtypes on GABAAR plays a role in the pathophysiology of CNS disorders such as schizophrenia, major depressive disorder (MDD), bipolar disorder and certain anxiety disorders such as OCD. The α5 subtypes in the lung play a major role in potential new treatments for asthma. Based on the privileged imidazodiazepine (IMZD) structures derived from the unified pharmacophore model of Milwaukee, the design, synthesis and biological activities of more than 120 novel chiral GABAAR α2/α3/α5 or α5 subtype selective imidazodiazepines (IMDZs) related to SH-053-2\u27F-R-CH3, and its enantiomer SH-053-2\u27F-S-CH3, as well as the key achiral ligand Hz-166 are described. The goal of this research is to develop new analogs with improved metabolic stability that also retain the desired biological properties with little or no side effects for the treatment of CNS disorders, as well as asthma. Several compounds from the α5 subtype selective group are anxiolytic, antidepressant, as well as pro-cognitive, and are targeted toward the treatment of major depressive disorders. About 20 grams of one lead compound (GL-II-73), and more than 80 analogs were designed, synthesized and evaluated. The α5 selective chiral lead amide, GL-II-73, looks very good in rodent models for the treatment of depression. It exhibited an excellent pharmacokinetic profile, as well as anti-depressant and anxiolytic activities in mice. This antidepressant effect has been realized with no side effects such as sedation nor motor impairment that benzodiazepine drugs would normally effect. In addition, the much sought after improved cognitive effects were clear in mice; this is a key in treating depression or schizophrenia. Examination of the data in the most recent study indicated that the administration of a single dose of GL-II-73 within 30 minutes could reverse the stress-induced or normal aging-related working memory deficits in old mice back up to 80-90 %, which is almost at the level of a young mouse. Whereas the old mice or stressed young mice will normally perform at about a level of 50-60 %. Furthermore, the brain cells, which had shrunk in older mice associated with aging, grew back (dendrites and spines) to a level that is similar to the young mice. This is extremely exciting and occurred after two months of the administration of GL-II-73 to the old mice in their drinking water. These results were presented by our collaborator, Dr. Etienne Sibille in an interview with the BBC, but also resulted in three papers and two patents. It is hoped the CAMH group of Sibille can push this project forward to human trials within two years as proposed. Additional research on these key compounds by several groups is ongoing. One can imagine the use of GL-II-73 or analogs in other neurodegenerative diseases of the CNS. After evaluation of a series of novel IMDZs that were α5 subtype selective for the treatment of asthma, one compound MIDD0301 (originally named GL-II-93) was found to be orally active and also as an inhalant in rodent asthma models. Ligand MIDD0301 was active in the airway smooth muscle (ASM) relaxation assay, in the airway hyper-responsiveness model, in the human and guinea pig tracheal bath assays. Moreover, it does not induce any immunotoxicity in animal models. Taken together this data suggests that this novel ligand can be a potential candidate for the treatment of asthma. About 50 grams of the ligand has been synthesized in good yield to support all the different biological assays from our collaborators. Furthermore, the large scale total synthesis of MIDD0301 was presented to the Alcami Corporation for a proposed kilogram scale synthesis of GMP material for further research on toxicity and safety. This research has resulted in three new publications over the last year. This compound provided some of the impetus to found a new company, Panthergenics, to try to get it through the FDA. Dr. Arnold and Dr. Stafford founded the company via UW-Milwaukee. In regard to the design of new α2/3 subtype selective agents to treat anxiety disorders, neuropathic pain and epilepsy, an improved large scale synthesis of Hz-166, MP-III-080, and KRM-II-81 was executed. These ligands are anxiolytic, anticonvulsant and antinociceptive agents. They were prepared under milder conditions and with much improved yields. Moreover, an alternative reduction process, which was developed for the synthesis of the key aldehyde intermediate from the ethyl ester, was optimized. This new process overcame the long-standing problem of imine reduction in good yield. These methods can be employed for larger scale reactions. In addition, there is no need for column chromatography for most of the compounds, which provided a much more practical route. With the improved synthesis, large quantities of these three α2/3-subtype selective GABAARs PAMs, which exhibited anxiolytic, anticonvulsant and antinociceptive effects in many animal tests, can be supplied with high-efficiency and quality to our collaborators. The large-scale synthesis and the analog research will permit investigation of ADME toxicity and for other behavior assays including those in primates. Studies in animal models for anxiety and epilepsy, as well as for neuropathic pain require gram quantities of compounds, which can now be provided. This will also permit the execution of long-term safety studies in order to approach the FDA

Design and implementation of an intelligent circuit analyzer

This paper designs a smart socket based on microcontroller and WIFI module. The socket can measure the voltage information and grounding of the connected circuit, display the measurement results and voice broadcast, and the user can also view the measurement results in real time through the cell phone APP, and design a transparent waterproof box for it to enhance its waterproof performance, which has certain significance to the safe use of electricity

A modulated model predictive control scheme for the brushless doubly-fed induction machine

This paper proposes a modulated model predictive control (MMPC) algorithm for a brushless double-fed induction machine. The Brushless Doubly-Fed Induction Machine has some important advantages over alternative solutions for brushless machine applications. The proposed modulation technique achieves a fixed switching frequency, which gives good system performance. The paper examines the design and implementation of the modulation technique and simulation results verify the operation of the proposed modulation technique

A Modulated Model Predictive Control Scheme for the Brushless Doubly Fed Induction Machine

© 2013 IEEE. Brushless doubly fed induction machines (BDFIMs) feature some important advantages, such as high reliability and low maintenance cost, over alternative solutions for brushless machine applications. This paper proposes a modulated model predictive control (MPC) algorithm for BDFIMs, which achieves a fixed switching frequency and superior system performance. An improvement of power quality is shown in this paper when compared to the conventional finite-control set-MPC. This paper examines the design and implementation of the modulation technique as well as presenting the simulation and experimental results to verify the technique's operation

Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide

We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with alpha 5 GABA(A) receptors (alpha 5GABA(A)Rs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of alpha 5GABA(A)Rs in offspring's preadolescence (from postnatal day 22-28) could prevent the deficit in locomotor reactivity to amphetamine observed in adulthood, at postnatal day P60. The elevation of IL-6 in amniotic fluid 6 h after LPS treatment (100 mu g/kg, i.p.) at E15 was concurrent with a significant increase of GABA and decrease of glutamate concentration in fetal brain. Moreover, repeated administration of MP-III-022, a selective positive allosteric modulator of alpha 5GABA(A)Rs, at a dose (2 mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5 mg/kg, i.p.) in adult females. These results were not mirrored in the parallel set of experiments with male offspring from LPS-treated rats. The results suggest that pharmacological potentiation of alpha 5GABA(A)Rs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero

Zolpidem Activation of Alpha 1-Containing GABAA Receptors Selectively Inhibits High Frequency Action Potential Firing of Cortical Neurons

Introduction: High frequency neuronal activity in the cerebral cortex can be induced by noxious stimulation during surgery, brain injury or poisoning. In this scenario, it is essential to block cortical hyperactivity to protect the brain against damage, e.g., by using drugs that act as positive allosteric modulators at GABAA receptors. Yet, cortical neurons express multiple, functionally distinct GABAA receptor subtypes. Currently there is a lack of knowledge which GABAA receptor subtypes would be a good pharmacological target to reduce extensive cortical activity.Methods: Spontaneous action potential activity was monitored by performing extracellular recordings from organotypic neocortical slice cultures of wild type and GABAAR-α1(H101R) mutant mice. Phases of high neuronal activity were characterized using peri-event time histograms. Drug effects on within-up state firing rates were quantified via Hedges’ g.Results: We quantified the effects of zolpidem, a positive modulator of GABAA receptors harboring α1-subunits, and the experimental benzodiazepine SH-053-2′F-S-CH3, which preferably acts at α2/3/5- but spares α1-subunits. Both agents decreased spontaneous action potential activity but altered the firing patterns in different ways. Zolpidem reduced action potential firing during highly active network states. This action was abolished by flumazenil, suggesting that it was mediated by benzodiazepine-sensitive GABAA receptors. SH-053-2′F-S-CH3 also attenuated neuronal activity, but unlike zolpidem, failed to reduce high frequency firing. To confirm that zolpidem actions were indeed mediated via α1-dependent actions, it was evaluated in slices from wild type and α(H101R) knock-in mice. Inhibition of high frequency action potential firing was observed in slices from wild type but not mutant mice.Conclusion: Our results suggest that during episodes of scarce and high neuronal activity action potential firing of cortical neurons is controlled by different GABAA receptor subtypes. Exaggerated firing of cortical neurons is reduced by positive modulation of α1-, but not α2/3/5-subunit containing GABAA receptors

Effects of moisture content on electrostatic sensing based mass flow measurement of pneumatically conveyed particles

Mass flow rate measurement of pneumatically conveyed particles is desirable for the optimal control of many industrial processes. The unpredicted variation of moisture content in particles affects the accuracy of mass flow measurement of particles in enclosed pipelines using electrostatic electrodes. In this study, the characteristics of measured electrostatic signals from particle flow under different flow conditions are analysed to study the effect of moisture content on the mass flow rate measurement. The measurement principle of ring-shaped electrostatic electrodes, the effects of moisture content on electrification of solid particles, and the experimental setup used in the study are presented. Two types of electrostatic electrodes with different axial widths and structure are adopted to measure the electrostatic signals of nonporous glass beads and porous activated carbon powder on the vertical pipeline of a 74 mm bore gas–solid two-phase flow test rig under various moisture content, mass flow rate and conveying velocity conditions. The experimental results indicate that the amplitude and frequency characteristics of the electrostatic signals change with the moisture content. The deviation of mass flow measurement that caused by the variation of moisture content is analysed, and a recalibration process is demonstrated to be effective for the improvement of measurement accuracy

Imidazodiazepine Anticonvulsant, KRM-II-81, Produces Novel, Non-diazepam-like Antiseizure Effects

The need for improved medications for the treatment of epilepsy and chronic pain is essential. Epileptic patients typically take multiple antiseizure drugs without complete seizure freedom, and chronic pain is not fully managed with current medications. A positive allosteric modulator (PAM) of α2/3-containing GABAA receptors (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81 (8) is a lead compound in a series of imidazodiazepines. We previously reported that KRM-II-81 produces broad-based anticonvulsant and antinociceptive efficacy in rodent models and provides a wider margin over motoric side effects than that of other GABAA receptor PAMs. The present series of experiments was designed to fill key missing gaps in prior preclinical studies assessing whether KRM-II-81 could be further differentiated from nonselective GABAA receptor PAMs using the anticonvulsant diazepam (DZP) as a comparator. In multiple chemical seizure provocation models in mice, KRM-II-81 was either equally or more efficacious than DZP. Most strikingly, KRM-II-81 but not DZP blocked the development of seizure sensitivity to the chemoconvulsants cocaine and pentylenetetrazol in seizure kindling models. These and predecessor data have placed KRM-II-81 into consideration for clinical development requiring the manufacture of kilogram amounts of good manufacturing practice material. We describe here a novel synthetic route amenable to kilogram quantity production. The new biological and chemical data provide key steps forward in the development of KRM-II-81 (8) as an improved treatment option for patients suffering from epilepsy

Life Cycle Assessment of Environmental Impact of Steelmaking Process

The steel industry is facing problems such as serious environmental pollution and high resource consumption. At the same time, it lacks effective methods to quantify potential environmental impacts. The purpose of this work is to conduct a specific environmental analysis of steelmaking production in steel plants. The ultimate goal is to discover the main pollution of steelmaking and identify potential options for improving the environment. This paper uses life cycle assessment method to carry out inventory and quantitative analysis on the environmental impact of steelmaking system. Through analysis, the hazards are divided into four major categories, which are human health, climate change, ecosystem quality, and resources. The results show that molten iron has the greatest impact on human health, followed by the greatest impact on resources. The impact of scrap steel on human health ranks third. Molten iron is a key process that affects human health, climate change, ecosystems quality, and resources. In addition, processes such as fuels, working fluids, and auxiliary materials also cause certain environmental damage, accounting for a relatively small proportion. Optimizing the utilization of scrap steel and molten iron resources and improving the utilization efficiency of resources and energy are helpful to reduce the environmental hazards of steelmaking system

Study on the Basic Mechanical Properties and Discrete Element Method Simulation of Permeable Concrete

Permeable concrete pavement material has many voids and a good water permeability, which can reduce surface runoff and alleviate the problem of urban water logging. It also has the functions of acting as a supplementary source of groundwater, purifying water, bodies reducing the urban heat island effect, reducing road noise, and so on. It is an effective solution for urban infrastructures. However, at the same time, because it has a large number of pores, this also affects the strength of permeable concrete. The main factors affecting permeable concrete are particle size and the shape of the aggregate, the content of the cement paste and aggregate, the compaction degree of the mixture, and so on. In this study, the single-factor test method was used to study the effects of aggregate size, slurry-to-bone ratio and loose paving coefficient on the basic mechanical properties and permeability of permeable concrete. Here, the numerical model for permeable concrete is established by using the particle flow discrete element (Particle Flow Code (PFC)modeling method, and a numerical simulation test is carried out. It can be seen from the test results that the permeability coefficient of 50% 5–10 mm + 50% 10–15 mm mixed aggregate permeable concrete is slightly lower than that of 5–10 mm and 10–15 mm single-size aggregate, but has a higher compressive and splitting tensile strength. With the increase in paste-to-bone ratio, the permeability coefficient of permeable concrete decreases, and the compressive strength increases. The loose paving coefficient has a significant effect on the mechanics and permeability of permeable concrete with the increase in the loose paving coefficient, the water permeability decreases and the compressive strength increases. The numerical simulation results show that under the condition that the loose paving coefficient is 1.10 and the slurry-to-bone ratio is 0.5, compared with the experimental results, the error of the numerical simulation results of the compression test is less than 3%. The reliability of the simulation is verified. The discrete element modeling method in this study can be used to simulate the shape of the aggregate in permeable concrete, and the numerical model can effectively simulate the crack development and failure form of permeable concrete in compression tests