Studies on the metabolism and toxicological detection of the new psychoactive designer drug 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe) in human and rat urine using GC-MS, LC-MSn, and LC-HR-MS/MS

25I-NBOMe, a new psychoactive substance, is a potent 5-HT2A receptor agonist with strong hallucinogenic potential. Recently, it was involved in several fatal and non-fatal intoxication cases. The aim of the present work was to study its phase I and II metabolism and its detectability in urine screening approaches. After application of 25I-NBOMe to male Wistar rats, urine was collected over 24 h. The phase I and II metabolites were identified by LC-HR-MS/MS in urine after suitable workup. For the detectability studies, standard urine screening approaches (SUSA) by GC-MS, LC-MSn, and LC-HR-MS/MS were applied to rat and also to authentic human urine samples submitted for toxicological analysis. Finally, an initial CYP activity screening was performed to identify CYP isoenzymes involved in the major metabolic steps. 25I-NBOMe was mainly metabolized by O-demethylation, O,O-bis-demethylation, hydroxylation, and combinations of these reactions as well as by glucuronidation and sulfation of the main phase I metabolites. All in all, 68 metabolites could be identified. Intake of 25I-NBOMe was detectable mainly via its metabolites by both LC-MS approaches, but not by the GC-MS SUSA. Initial CYP activity screening revealed the involvement of CYP1A2 and CYP3A4 in hydroxylation and CYP2C9 and CYP2C19 in O-demethylation. The presented study demonstrated that 25I-NBOMe was extensively metabolized and could be detected only by the LC-MS screening approaches. Since CYP2C9 and CYP3A4 are involved in initial metabolic steps, drug–drug interactions might occur in certain constellations

Synthesis, characterization, monolayer assembly and 2D lanthanide coordination of a linear terphenyl-di(propiolonitrile) linker on Ag(111)

As a continuation of our work employing polyphenylene-dicarbonitrile molecules and in particular the terphenyl derivative 1 (TDCN), we have synthesized a novel ditopic terphenyl-4,4”-di(propiolonitrile) (2) linker for the self-assembly of organic monolayers and metal coordination at interfaces. The structure of the organic linker 2 was confirmed by single crystal X-ray diffraction analysis (XRD). On the densely packed Ag(111) surface, the terphenyl-4,4”-di(propiolonitrile) linkers self-assemble in a regular, molecular chevron arrangement exhibiting a Moire pattern. After the exposure of the molecular monolayer to a beam of Gd atoms, the propiolonitrile groups get readily involved in metal-ligand coordination interactions. Distinct coordination motifs evolve with coordination numbers varying between three and six for the laterally-bound Gd centers. The linker molecules retain an overall flat adsorption geometry. However, only networks with restricted local order were obtained, in marked contrast to previously employed, simpler polyphenylene-dicarbonitrile 1 linkers

Exchange splitting of the three Γ¯ surface states of Ni(111) from three-dimensional spin- and angle-resolved photoemission spectroscopy

The valence-band electronic structure of a clean Ni(111) surface is investigated by spin-resolved photoemission. At room temperature the orientation of the photoelectron spins on the Bloch sphere and the exchange splitting of surface and bulk states along the surface normal (Γ̅ ) are determined. All investigated states are found to have a sizable exchange splitting >50 meV. Since the splitting is smaller than the intrinsic line width in the spin-integrated spectrum this is only seen with a spin-resolved technique. At room-temperature photoemission reaching above the Fermi level directly shows that the Shockley type surface state S1 has an occupied majority and an unoccupied minority band with a splitting ΔEex=62±15 meV. The surface states below the Fermi energy show a larger exchange splitting for in-plane hybridization [ΔEex(S3)=160 meV] than for out-of-plane hybridization [ΔEex(S2)=55 meV]

Selective Supramolecular Fullerene-Porphyrin Interactions and Switching in Surface-Confined C-60-Ce(TPP)(2) Dyads

The control of organic molecules, supramolecular complexes and donor acceptor systems at interfaces is a key issue in the development of novel hybrid architectures for regulation of charge-carrier transport pathways in nano-electronics or organic photovoltaics. However, at present little is known regarding the intricate features of stacked molecular nanostructures stabilized by noncovalent interactions. Here we explore at the single molecule level the geometry and electronic properties of model donor-acceptor dyads stabilized by van der Waals interactions on a single crystal Ag(111) support. Our combined scanning tunneling microscopy/spectroscopy (STM/STS) and first-principles computational modeling study reveals site-selective positioning of C-60 molecules on Ce(TPP)(2) porphyrin double-decker arrays with the fullerene centered on the pi-system of the top bowl-shaped tetrapyrrole macroc-ycle. Three specific orientations of the C-60 cage in the van der Waals complex are identified that can be reversibly switched by STM manipulation protocols. Each configuration presents a distinct conductivity, which accounts for a tristable molecular switch and the tunability of the intradyad coupling. In addition, STS data evidence electronic decoupling of the hovering C-60 units from the metal substrate, a prerequisite for photophysical applications

Measurement of direct ethanol metabolites in a case of a former driving under the influence (DUI) of alcohol offender, now claiming abstinence

A 37-year-old female subject had been convicted of driving under the influence of alcohol, and 19 months later, claimed abstinence after supervised disulfiram treatment. Our aim was to elucidate the value of direct ethanol metabolites as measures of abstinence. Ethyl glucuronide (EtG) and fatty acid ethyl esters (FAEE) in hair, phosphatidylethanol in whole blood and EtG and ethyl sulphate in urine were measured. The results were compared with self-report of alcohol consumption and traditional blood biomarkers for chronically elevated alcohol consumption as carbohydrate deficient transferrin (CDT), gamma glutamyl transpeptidase, mean corpuscular erythrocyte volume, aspartate aminotransferase and alanine aminotransferase. EtG was found in distal parts of hair only, whereas the proximal parts were negative. Furthermore, FAEE concentrations were found in the typical distribution over the hair length and showed values typical for either moderate social drinking or abstinence. CDT was above cut-off in 9 out of 16 analyses with a decreasing tendency and the lowest values in the last 2 months before the end of sampling. The data suggest that in addition to traditional markers, a combination of direct ethanol metabolites can be useful in the expert assessment of judging driving ability. A careful individual interpretation of the results for the different markers, however, is an absolute necessity

On-Surface Synthesis of Polyphenylene Wires Comprising Rigid Aliphatic Bicyclo[1.1.1]Pentane Isolator Units

Bicyclo[1.1.1]pentane (BCP) motifs are of growing importance to the pharmaceutical industry as sp(3)-rich bioisosteres of benzene rings and as molecular building blocks in materials science. Herein we explore the behavior of 1,3-disubstituted BCP moieties on metal surfaces by combining low-temperature scanning tunneling microscopy / non-contact atomic force microscopy studies with density functional theory modeling. We examine the configuration of individual BCP-containing precursors on Au(111), their supramolecular assembly and thermally activated dehalogenative coupling reactions, affording polymeric chains with incorporated electronically isolating units. Our studies not only provide the first sub-molecular insights of the BCP scaffold behavior on surfaces, but also extend the potential application of BCP derivatives towards integration in custom-designed surface architectures.Funding Agencies|Technical University of Munich-Institute for Advanced Study through a Hans Fischer Senior Fellowship; Science Foundation Ireland (SFI) [21/FFP-A/9469]; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [453903355]; Swedish research council; Bavarian state ministry for education, science, and the arts visiting professor program; Projekt DEAL</p

Assessment of alcohol use among methadone maintenance patients by direct ethanol metabolites and self-reports

BACKGROUND: Heavy alcohol consumption may accelerate the progression of hepatitis C (HCV)-related liver disease and/or limit efforts at antiviral treatment. As most of the patients in methadone maintenance treatment (MMT) suffer from hepatitis C infection, this study was conducted to identify the alcohol intake among these patients at a Swiss Psychiatric University Clinic by self-reports and direct ethanol metabolites as biomarkers of ethanol consumption. PATIENTS AND METHODS: A convenience sample of 40 MMT patients (15 women, 25 men; median age 39 years) of the total 124 patients was asked and consented to participate in this study. This sample was not different in age, gender distribution, and rate of hepatitis C infection from the total sample. The Alcohol Use Disorders Identification Test (AUDIT) and self-reported ethanol intake during the previous 7 days were assessed. In addition, ethyl glucuronide (EtG) in urine, and fatty acid ethyl esters (FAEEs) and EtG in hair were determined using LC-MS/MS and gas chromatograph/mass spectrometer. The limit of quantitation for UEtG, HEtG, and FAEEs were 0.1 mg/l, 2.3 pg/mg, and 0.1 ng/mg, respectively. RESULTS: Fourteen participants reported abstinence from alcohol for the previous 7 days. AUDIT scores were > or =8 in 15 male and >5 in 5 female participants. Direct ethanol metabolites were as follows (median, min, max, standard deviation): UEtG (19 positives; 9.91, 1.38 to 251, 62.39 mg/l); the values of HEtG were 17.65, 0 to 513, 105.62 pg/mg [in 2 cases no material, 8 abstinent (up to 7 pg/mg), 15 social drinkers (up to 50 g per day), and 15 excessive users (>50/60 g/d)]. For the 13 cases, where enough material for additional determination of HFAEEs was available, the values were 0.32, 0 to 1.32, 0.44 ng/mg. Among the 30 HEtG-positive participants, 20 had not reported the corresponding ethanol intake using question 1 (frequency) and 2 (quantity) of the AUDIT. Of the 14 participants reporting no alcohol intake during the previous 7 days, 4 were UEtG-positive. HEtG and AUDIT correlated significantly (r = 0.622, p < 0.0001), but this was not the case for UEtG and self-reported ethanol intake during the previous 7 days. CONCLUSION: (1) HEtG identified 20 cases of daily ethanol intake of more than 20 g, that would have been missed by the sole use of question 1 (frequency) and 2 (quantity) of the AUDIT. (2) Using the total score of the AUDIT, HEtG confirmed 10 more cases positive for alcohol intake. (3) Episodic heavy drinking is with 22.5% more frequent than in general population, and (4) of the 14 participants who reported no alcohol intake during the previous 7 days, 4 were UEtG positive. Improved detection of alcohol consumption, which is hazardous or harmful in the context of HCV and opiate dependence, would allow for earlier intervention in this population which is at particular risk of liver disease and fatal respiratory-depressed overdose. The combined use of self-reports and direct ethanol metabolites seems promising

Boron nitride on Cu(111): an electronically corrugated monolayer

Ultrathin films of boron nitride (BN) have recently attracted considerable interest given their successful incorporation in graphene nanodevices and their use as spacer layers. to electronically decouple and order functional adsorbates. Here, we introduce a BN monolayer grown by chemical Vapor deposition of borazine on a single crystal Cu support, representing a model system for an electronically patterned but topographically smooth substrate. Scanning tunneling microscopy and spectroscopy experiments evidence a weak bonding Of the single BN sheet to Cu, preserving the insulating character of bulk hexagonal boron nitride combined with a periodic lateral variation of the local work function and the surface potential. Complementary, density functional theory calculations reveal a varying registry of the BN relative to the Cu lattice as origin of this electronic Moire-like superstructure