GW 803430

Accurate description of the electronic structure of organic semiconductors by GW methods.[Pubmed:28145283]

J Phys Condens Matter. 2017 Mar 15;29(10):103003.

Electronic properties associated with charged excitations, such as the ionization potential (IP), the electron affinity (EA), and the energy level alignment at interfaces, are critical parameters for the performance of organic electronic devices. To computationally design organic semiconductors and functional interfaces with tailored properties for target applications it is necessary to accurately predict these properties from first principles. Many-body perturbation theory is often used for this purpose within the GW approximation, where G is the one particle Green's function and W is the dynamically screened Coulomb interaction. Here, the formalism of GW methods at different levels of self-consistency is briefly introduced and some recent applications to organic semiconductors and interfaces are reviewed.

High average power nonlinear compression to 4 GW, sub-50 fs pulses at 2 mum wavelength.[Pubmed:28198855]

Opt Lett. 2017 Feb 15;42(4):747-750.

The combination of high-repetition-rate ultrafast thulium-doped fiber laser systems and gas-based nonlinear pulse compression in waveguides offers promising opportunities for the development of high-performance few-cycle laser sources at 2 mum wavelength. In this Letter, we report on a nonlinear pulse compression stage delivering 252 muJ, sub-50 fs-pulses at 15.4 W of average power. This performance level was enabled by actively mitigating ultrashort pulse propagation effects induced by the presence of water vapor absorptions.

Quantitative characterization of exciton from GW+Bethe-Salpeter calculation.[Pubmed:28147542]

J Chem Phys. 2017 Jan 28;146(4):044303.

We propose a method of classifying excitons into local-, Rydberg-, or charge transfer-type as a step toward enabling a data-driven material design of organic solar cells. The classification method is based on the first-principles many-body theory and improves over the conventional method based on state-by-state visualization of the one-electron wave functions. In our method, the exciton wave function is calculated within the level of the GW+Bethe-Salpeter equation, which is used to obtain two dimensionless parameters for the automatic classification. We construct criteria for exciton classification from experiences with a model molecule, dipeptide. Then we check the validity of our method using a model beta-dipeptide which has a geometry and an excitation spectrum similar to the model dipeptide. In addition, we test the effectiveness of the method using porphyrin molecules, or P1TA and P2TA, for which the conventional method is hampered by the strong state hybridization associated with excitation. We find that our method works successfully for P1TA, but the analysis of P2TA is hindered by its centrosymmetry.

GW-SEM: A Statistical Package to Conduct Genome-Wide Structural Equation Modeling.[Pubmed:28299468]

Behav Genet. 2017 May;47(3):345-359.

Improving the accuracy of phenotyping through the use of advanced psychometric tools will increase the power to find significant associations with genetic variants and expand the range of possible hypotheses that can be tested on a genome-wide scale. Multivariate methods, such as structural equation modeling (SEM), are valuable in the phenotypic analysis of psychiatric and substance use phenotypes, but these methods have not been integrated into standard genome-wide association analyses because fitting a SEM at each single nucleotide polymorphism (SNP) along the genome was hitherto considered to be too computationally demanding. By developing a method that can efficiently fit SEMs, it is possible to expand the set of models that can be tested. This is particularly necessary in psychiatric and behavioral genetics, where the statistical methods are often handicapped by phenotypes with large components of stochastic variance. Due to the enormous amount of data that genome-wide scans produce, the statistical methods used to analyze the data are relatively elementary and do not directly correspond with the rich theoretical development, and lack the potential to test more complex hypotheses about the measurement of, and interaction between, comorbid traits. In this paper, we present a method to test the association of a SNP with multiple phenotypes or a latent construct on a genome-wide basis using a diagonally weighted least squares (DWLS) estimator for four common SEMs: a one-factor model, a one-factor residuals model, a two-factor model, and a latent growth model. We demonstrate that the DWLS parameters and p-values strongly correspond with the more traditional full information maximum likelihood parameters and p-values. We also present the timing of simulations and power analyses and a comparison with and existing multivariate GWAS software package.

Preclinical evaluation of melanin-concentrating hormone receptor 1 antagonism for the treatment of obesity and depression.[Pubmed:19182070]

J Pharmacol Exp Ther. 2009 May;329(2):429-38.

The mammalian neuropeptide, melanin-concentrating hormone, interacts with two G protein-coupled receptors, melanin-concentrating hormone receptor (MCHR) 1 and MCHR2; however, only MCHR1 is expressed in rats and mice. In the present study, we evaluated MCHR1 antagonism in preclinical models believed to be predictive of antiobesity and antidepressant activity. Central activity of the selective MCHR1 antagonist, GW803430 [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[ 3,2-d]pyrimidin-4-one], was evaluated using ex vivo binding with autoradiography. Effective doses of GW803430 (1 and 3 mg/kg p.o.) were correlated with antiobesity activity in a 14-day study of diet-induced obese rats. GW803430 was evaluated subsequently for antidepressant-like effects in mice and rats. Acute and subchronic administration reduced immobility time in the mouse forced-swim test at doses of 3 (acute) and 3 and 10 (chronic) mg/kg p.o., an effect that was absent in MCHR1(-/-) mice. Combined subeffective doses of GW803430 (0.3 and 1 mg/kg p.o.) and imipramine (5 mg/kg) produced a robust antidepressant-like response. The compound was also active in the tail suspension test at a dose of 10 mg/kg p.o. GW803430 (30 mg/kg p.o.) significantly reduced submissive behaviors at weeks 2 and 3, a model of submissive behavior that may predict antidepressant onset. GW803430 decreased marble burying in mice at doses of 3, 10, and 30 mg/kg p.o., an assay that detects anxiolytic-like effects. Thus, GW803430 produces robust antiobesity and antidepressant-like effects in rats and mice at doses that compete for central MCHR1 in vivo. As such, MCHR1 should be considered as a promising target for future drug discovery efforts.

Melanin-concentrating hormone receptor 1 antagonists: a new perspective for the pharmacologic treatment of obesity.[Pubmed:18393860]

Curr Med Chem. 2008;15(10):1025-43.

Obesity is a chronic disease characterized by the accumulation of excess adipose tissue associated with an increased risk of multiple morbidities and mortality. At the present time, only three drugs have been approved by the Food and Drug Administration (FDA) for the treatment of obesity. Agonists and antagonists of some of the substances implicated in the regulation of energy homeostasis represent opportunities for anti-obesity drug development. The most promising targets are alpha-melanocyte stimulating hormone (alpha-MSH) receptors, cannabinoid receptors, the 5-hydroxytryptamine (5-HT) receptors and melanin-concentrating hormone (MCH) receptors. MCH receptors could be major potential targets for the treatment of obesity. Many pharmaceutical companies have described MCH-R1 antagonists that have appeared over the past year. Recently, two compounds went into phase I clinical trials that evaluate MCH receptor antagonists as a new perspective for the pharmacologic treatment of obesity. In this review, structure-activity relationships (SAR) in the development of MCH-R1 antagonists are provided.

GW-803430 (GW-3430) is a potent and selective melanin-concentrating hormone receptor 1 (MCH R1) antagonist with a pIC50 of 9.3. GW-803430 is orally active in an animal model of obesity.

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