Metabolism of synthetic cannabinoids PB-22 and its 5-fluoro analog, 5F-PB-22, by human hepatocyte incubation and high-resolution mass spectrometry

Background

PB-22 (1-pentyl-8-quinolinyl ester-1H-indole-3-carboxylic acid) and 5F-PB-22 (1-(5-fluoropentyl)-8-quinolinyl ester-1H-indole-3-carboxylic acid) are new synthetic cannabinoids with a quinoline substructure and the first marketed substances with an ester bond linkage. No human metabolism data are currently available, making it difficult to document PB-22 and 5F-PB-22 intake from urine analysis, and complicating assessment of the drugs’ pharmacodynamic and toxicological properties.

Methods

We incubated 10 μmol/l PB-22 and 5F-PB-22 with pooled cryopreserved human hepatocytes up to 3 h and analyzed samples on a TripleTOF 5600+ high-resolution mass spectrometer. Data were acquired via TOF scan, followed by information-dependent acquisition triggered product ion scans with mass defect filtering (MDF). The accurate mass full scan MS and MS/MS metabolite datasets were analyzed with multiple data processing techniques, including MDF, neutral loss and product ion filtering.

Results

The predominant metabolic pathway for PB-22 and 5F-PB-22 was ester hydrolysis yielding a wide variety of (5-fluoro)pentylindole-3-carboxylic acid metabolites. Twenty metabolites for PB-22 and 22 metabolites for 5F-PB-22 were identified, with the majority generated by oxidation with or without glucuronidation. For 5F-PB-22, oxidative defluorination occurred forming PB-22 metabolites. Both compounds underwent epoxide formation followed by internal hydrolysis and also produced a cysteine conjugate.

Conclusion

Human hepatic metabolic profiles were generated for PB-22 and 5F-PB-22. Pentylindole-3-carboxylic acid, hydroxypentyl-PB-22 and PB-22 pentanoic acid for PB-22, and 5′-fluoropentylindole-3-carboxylic acid, PB-22 pentanoic acid and the hydroxy-5F-PB-22 metabolite with oxidation at the quinoline system for 5F-PB-22 are likely the best targets to incorporate into analytical methods for urine to document PB-22 and 5F-PB-22 intake.

The influence of pairing and nuclear structure on the thermal-neutron-induced fission of235U

The mass separated fission product beam provided by the mass separator “Lohengrin” has been used to determine the nuclear charge distribution for the thermal-neutron-induced fission of²³⁵U for all light fission products in the region 80≦A≦107. The measurements were performed at the most probable kinetic energy of the fission products. By using the known fission product mass yields, the independent yields for a total number of 100 nuclides were obtained under the condition of the most probable kinetic energy. The proton pairing effect modulates the average nuclear charge of the fission fragments and the isobaric charge distribution widths in a regular fashion. The probabilities of breaking a pair and of forming fragments with an energetically unfavourable neutron-to-proton ratio are found to compete with each other. Both probabilities depend on the mass split and reach their maximum values in the region of the most probable masses. The odd-even-proton effect is found to vary smoothly between 16% for the most abundant mass splits and 40% for the rare mass splits. The odd-even-neutron effect exhibits maxima nearN=50 andN=60, where it reaches 16%. These maxima and the extremely low Tcyield (0.13±0.05%) are discussed with regard to fragment shell effects.     

Accelerating cosmologies from compactification

A solution of the (4+n)-dimensional vacuum Einstein equations is found for which spacetime is compactified on an n-dimensional compact hyperbolic manifold (n> or =2) of time-varying volume to a flat four-dimensional Friedmann-Lemaitre-Robertson-Walker cosmology undergoing a period of accelerated expansion in the Einstein conformal frame. This shows that the "no-go" theorem forbidding acceleration in "standard" (time-independent) compactifications of string or M theory does not apply to "cosmological" (time-dependent) hyperbolic compactifications.     

LC-MS/MS screening method for designer amphetamines, tryptamines, and piperazines in serum

Since the late 1990s and early 2000s, derivatives of well-known designer drugs as well as new psychoactive compounds have been sold on the illicit drug market and have led to intoxications and fatalities. The LC-MS/MS screening method presented covers 31 new designer drugs as well as cathinone, methcathinone, phencyclidine, and ketamine which were included to complete the screening spectrum. All but the last two are modified molecular structures of amphetamine, tryptamine, or piperazine. Among the amphetamine derivatives are cathinone, methcathinone, 3,4-DMA, 2,5-DMA, DOB, DOET, DOM, ethylamphetamine, MDDMA, 4-MTA, PMA, PMMA, 3,4,5-TMA, TMA-6 and members of the 2C group: 2C-B, 2C-D, 2C-H, 2C-I, 2C-P, 2C-T-2, 2C-T-4, and 2C-T-7. AMT, DPT, DiPT, MiPT, DMT, and 5MeO-DMT are contained in the tryptamine group, BZP, MDBP, TFMPP, mCPP, and MeOPP in the piperazine group. Using an Applied Biosystems LC-MS/MS API 365 TurboIonSpray it is possible to identify all 35 substances. After addition of internal standards and mixed-mode solid-phase extraction the analytes are separated using a Synergi Polar RP column and gradient elution with 1 mM ammonium formate and methanol/0.1% formic acid as mobile phases A and B. Data acquisition is performed in MRM mode with positive electro spray ionization. The assay is selective for all tested substances. Limits of detection were determined by analyzing S/N-ratios and are between 1.0 and 5.0 ng/mL. Matrix effects lie between 65% and 118%, extraction efficiencies range from 72% to 90%.     

Covariant canonical quantization

We present a manifestly covariant quantization procedure based on the de Donder–Weyl Hamiltonian formulation of classical field theory. This procedure agrees with conventional canonical quantization only if the parameter space is d=1 dimensional time. In d>1 quantization requires a fundamental length scale, and any bosonic field generates a spinorial wave function, leading to the purely quantum-theoretical emergence of spinors as a byproduct. We provide a probabilistic interpretation of the wave functions for the fields, and we apply the formalism to a number of simple examples. These show that covariant canonical quantization produces both the Klein–Gordon and the Dirac equation, while also predicting the existence of discrete towers of identically charged fermions with different masses. Covariant canonical quantization can thus be understood as a “first” or pre-quantization within the framework of conventional QFT. PACS 04.62.+v; 11.10.Ef; 12.10.Kt     

The break-up reaction p0 + d → p1 + p2+ n at E0 = 16 MeV

The break-up reaction p₀ + d → p₁ + p₂ + n has been studied at E₀ = 16 MeV in kinematically complete p₁-p₂ coincidence experiments with special regard to n-p final-state interactions (f.s.i.) and p₁-p₂ quasifree scattering (q.f.s.). The absolute differential cross section has been measured for n-p f.s.i. c.m. production angles from 60° to 140° and for four pairs of angles with strong contributions due to q.f.s. Calculations with separable nucleon-nucleon potentials based on the Faddeev equations are in good agreement with the data obtained. In general, the shape of the experimental differential cross section is well reproduced. Discrepancies of up to 30 % in the worst cases arise between the absolute values of the theoretical predictions and the experimental data.     

High magnetic field effects in some metallic magnetic materials

An account is given of the following magnetic properties in high magnetic fields: (1) Magnetic isotherms of pure nickel and Ni-Pd alloys near the Curie points; the exchange splitting energies deduced on this basis are discussed. (2) Metamagnetic transitions in internal fields for the rare earth-cobalt compounds R Co₂. (3) Metamagnetic transitions in external fields for Co(S, Se)₂ and ordered FePt₃.     

Magnetic and transport properties of the intermetallic compound Y4Co3

The susceptibility, magnetization, electrical resistivity and thermopower of Y₄Co₃ have been measured and a Curie temperature of (8±1) K has been observed. The results are interpreted in terms of localized d-electrons on some cobalt sites and itinerant d-electrons on the others.     

Experimental evidence for the influence of the atomic shell structure on the energy loss of high energy heavy ions in matter

Secondary electron yield measurements for ²⁵²Cf fission products in carbon foils reveal significant deviations for the electronic stopping cross section from semiempirical predictions. This effect may correspond to the Z₁ oscillations observed previously at much lower ion velocities.