Crystallographic characterization of three cathinone hydrochlorides new on the NPS market: 1-(4-methylphenyl)-2-(pyrrolidin-1-yl)hexan-1-one (4-MPHP), 4-methyl-1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one (α-PiHP) and 2-(methylamino)-1-(4-methylphenyl)pentan-1-one (4-MPD)

Cathinones belong to a group of compounds of great interest in the new psychoactive substances (NPS) market. Constant changes to the chemical structure made by the producers of these compounds require a quick reaction from analytical laboratories in ascertaining their characteristics. In this article, three cathinone derivatives were characterized by X-ray crystallography. The investigated compounds were confirmed as: 1-[1-(4-methylphenyl)-1-oxohexan-2-yl]pyrrolidin-1-ium chloride ( 1 , C₁₇H₂₆NO⁺·Cl^?, the hydrochloride of 4-MPHP), 1-(4-methyl-1-oxo-1-phenylpentan-2-yl)pyrrolidin-1-ium chloride ( 2 ; C₁₆H₂₄NO⁺·Cl^?, the hydrochloride of α-PiHP) and methyl[1-(4-methylphenyl)-1-oxopentan-2-yl]azanium chloride ( 3 ; C₁₃H₂₀NO⁺·Cl^?, the hydrochloride of 4-MPD). All the salts crystallize in a monoclinic space group: 1 and 2 in P2₁/c, and 3 in P2₁/n. To the best of our knowledge, this study provides the first detailed and comprehensive crystallographic data on salts 1 – 3 .     

NPS用户群网络感知保障运营体系研究

介绍当前用户网络感知问题及解决手段,提出一种提升NPS(净推荐值)用户群网络感知的综合解决方案。创新建立一种客户感知Qo E(体验质量)得分模型,从用户控制面与业务面建立用户对网络感知的得分体系。同时提出一种NPS识别模型,实现NPS网络感知闭环管理流程,通过挖掘Qo E得分低的NPS质差用户,聚类用户共性问题。针对指标劣化产生的告警,深入分析原因并协助维护人员和厂家快速定界定位问题,提升客户网络感知。     

Interpreting divergences and Madelung-type sums via extrapolations of sequence generating polynomials: Method of intersection and area rule

Based on explorations in estimating certain Madelung constants, we put forward here two separate strategies to understand the meaning of two distinct classes of divergent non-power-series expansions. One class refers to alternating series representations, the other to monotonic ones. They chiefly rest on precise and approximate polynomial extrapolations, depending on situations. In case of sawtooth sequences, e.g., the partial-sums obtainable from Dirichlet eta or beta function at negative integer arguments, exact sequence-generating polynomials are found. Extrapolations yield a graphical meaning to anti-limit here, along with the exact answer. For staircase sequences, like the ones obtained from partial-sums of series representations for lambda and zeta functions, again at negative integer arguments, anti-limits do not exist. But, correct sequence-generating polynomials are obtained. There, our recipe relies on estimation of specific, finite areas embedded by such polynomials. The schemes put forward here are direct, independent and conceptually appealing. A subsequent extension of the latter strategy to alternating series also lends extra credence. Two new interpretations of summability are gained. Pilot calculations on several types of lattice sums reveal the worth of our endeavor with approximate extrapolations as well.     

TD-SCDMA系统无线传播模型校正

无线传播模型是网络建设的基础,是小区规划的重要部分,是整个网络规划的基础。在TD-SCDMA系统基站大规模建设之际,合适的传播模型尤为重要。本文介绍了传播模型校正的关键技术,根据广东移动某市区TD-SCDMA系统网络规划,详细阐述模型校正的整个过程,给出了CW测试的细节,最后得出了适合当地的校正结果。     

EASI‐IMS an expedite and secure technique to screen for 25I‐NBOH in blotter papers

The increasing number of new psychoactive substances (NPS) and their quick worldwide spreading, often only slightly modified in the form of new derivatives and analogues, have brought the need for fast, wide‐ranging, and unequivocal identification methods in clinical and forensic investigations. Because it usually provides secure results, gas chromatography coupled to mass spectrometry (GC‐MS) has been routinely employed as the standard technique for the detection of NPS in blotter papers. For 25I‐NBOH (N‐(2‐hydroxybenzyl)‐2‐(4‐iodo‐2,5‐dimethoxyphenyl)ethan‐1‐aminium), however, GC‐MS analysis of an blotter paper extract leads to incorrect results. In this work, we investigated whether easy ambient sonic‐spray mass spectrometry imaging (EASI‐IMS), and ambient ionization MS method can be applied directly to the surface of the sample requiring therefore no extraction or sample preparations, would serve as an efficient, sensitive, and secure alternative for 25I‐NBOH screening.     

Allosteric Binding of MDMA to the Human Serotonin Transporter (hSERT) via Ensemble Binding Space Analysis with ΔG Calculations,Induced Fit Docking and Monte Carlo Simulations

Despite the recent promising results of MDMA (3,4-methylenedioxy-methamphetamine) as a psychotherapeutic agent and its history of misuse, little is known about its molecular mode of action. MDMA enhances monoaminergic neurotransmission in the brain and its valuable psychoactive effects are associated to a dual action on the 5-HT transporter (SERT). This drug inhibits the reuptake of 5-HT (serotonin) and reverses its flow, acting as a substrate for the SERT, which possesses a central binding site (S1) for antidepressants as well as an allosteric (S2) one. Previously, we characterized the spatial binding requirements for MDMA at S1. Here, we propose a structure-based mechanistic model of MDMA occupation and translocation across both binding sites, applying ensemble binding space analyses, electrostatic complementarity, and Monte Carlo energy perturbation theory. Computed results were correlated with experimental data (r = 0.93 and 0.86 for S1 and S2, respectively). Simulations on all hSERT available structures with Gibbs free energy estimations (ΔG) revealed a favourable and pervasive dual binding mode for MDMA at S2, i.e., adopting either a 5-HT or an escitalopram-like orientation. Intermediate ligand conformations were identified within the allosteric site and between the two sites, outlining an internalization pathway for MDMA. Among the strongest and more frequent interactions were salt bridges with Glu494 and Asp328, a H-bond with Thr497, a π-π with Phe556, and a cation-π with Arg104. Similitudes and differences with the allosteric binding of 5-HT and antidepressants suggest that MDMA may have a distinctive chemotype. Thus, our models may provide a framework for future virtual screening studies and pharmaceutical design and to develop hSERT allosteric compounds with a unique psychoactive MDMA-like profile.     

Analgesic Characteristics of NanoBEO Released by an Airless Dispenser for the Control of Agitation in Severe Dementia

Chronic pain is one of the most common causes of the need for clinical evaluation, acquiring more importance in the elderly with cognitive impairment. Reduced self-reporting capabilities cause unrelieved pain contributing to the development of agitation. Safe and effective pain treatment can afford the management of agitation without the serious increase in death risk associated with neuroleptics. To this aim, the essential oil of bergamot (BEO), proven by rigorous evidence to have strong preclinical anti-nociceptive and anti-allodynic properties, has been engineered (NanoBEO, patent EP 4003294) to allow randomized, double-blind, placebo-controlled trials (BRAINAID, {"type":"clinical-trial","attrs":{"text":"NCT04321889","term_id":"NCT04321889"}}NCT04321889). The present study: (1) assesses the analgesic effects of a single therapeutic dose of NanoBEO, as supplied by an airless dispenser for clinical translation, in models of inflammatory, neuropathic, and sensitization types of pain relevant to clinic; (2) provides a dose–response analysis of the efficacy of NanoBEO on scratching behavior, a typical behavioral disturbance occurring in dementia. A single therapeutic dose of NanoBEO confirms efficacy following thirty minutes pre-treatment with capsaicin and on the central sensitization phase induced by formalin. Moreover, it has an ID50 of 0.6312 mg and it is efficacious on static and dynamic mechanical allodynia. Altogether, the gathered results strengthen the potential of NanoBEO for clinical management of pain and agitation.     

A dimethylzinc/diphenylphosphinoylimine approach to the asymmetric synthesis of the calcimimetic agent NPS R‐568

An asymmetric synthesis of the calcimimetic agent NPS R‐568 using a (1R,2S)‐N‐benzylephedrine‐promoted addition of dimethylzinc to a diphenylphosphinoylimine derived from 3‐methoxybenzaldehyde is described. The enantiomeric ratio of the key amine fragment was determined to be 93:7 (86% ee), favoring the (R)‐enantiomer by derivatization and chiral stationary phase HPLC analysis. Copyright © 2010 John Wiley & Sons, Ltd.     

Accident at the Fukushima Dai-ichi Nuclear Power Stations of TEPCO —Outline & lessons learned—

The severe accident that broke out at Fukushima Dai-ichi nuclear power stations on March 11, 2011, caused seemingly infinite damage to the daily life of residents. Serious and wide-spread contamination of the environment occurred due to radioactive materials discharged from nuclear power stations (NPSs). At the same time, many issues were highlighted concerning countermeasures to severe nuclear accidents. The accident is outlined, and lessons learned are extracted with respect to the safety of NPSs, as well as radiation protection of residents under the emergency involving the accident. The materials of the current paper are those released by governmental agencies, academic societies, interim reports of committees under the government, and others.     

Low resolution and high resolution MS for studies on the metabolism and toxicological detection of the new psychoactive substance methoxypiperamide (MeOP)

In 2013, the new psychoactive substance methoxypiperamide (MeOP) was first reported to the European Monitoring Centre for Drug and Drug Addiction. Its structural similarity to already controlled piperazine designer drugs might have contributed to the decision to offer MeOP for online purchase. The aims of this work were to identify the phase I/II metabolites of MeOP in rat urine and the human cytochrome P450 (CYP) isoenzymes responsible for the initial metabolic steps. Finally, the detectability of MeOP in rat urine by gas chromatography–mass spectrometry (GC‐MS) and liquid chromatography coupled with multistage mass spectrometry (LC‐MSⁿ) standard urine screening approaches (SUSAs) was evaluated. After sample preparation by cleavage of conjugates followed by extraction for elucidating phase I metabolites, the analytes were separated and identified by GC‐MS as well as liquid chromatography‐high resolution‐tandem mass spectrometry (LC‐HR‐MS/MS). For detection of phase II metabolites, the analytes were separated and identified after urine precipitation followed by LC‐HR‐MS/MS. The following metabolic steps could be postulated: hydrolysis of the amide, N‐oxide formation, N‐ and/or O‐demethylation, oxidation of the piperazine ring to the corresponding keto‐piperazine, piperazine ring opening followed by oxidation of a methylene group to the corresponding imide, and hydroxylation of the phenyl group. Furthermore, N‐acetylation, glucuronidation and sulfation were observed. Using human CYPs, CYP1A2, CYP2C19, CYP2D6, and/or CYP3A4 were found to catalyze N‐oxide formation and N‐, O‐demethylation and/or oxidation. Mostly MeOP and N‐oxide‐MeOP but to a minor degree also other metabolites could be detected in the GC‐MS and LC‐MSⁿ SUSAs. Copyright © 2015 John Wiley & Sons, Ltd.