24 research outputs found
Effects of α‐Pyrrolidinopentiophenone and 4-Methyl-N-Ethylcathinone, Two Synthetic Cathinones Commonly Found in Second-Generation “Bath Salts,” on Intracranial Self-Stimulation Thresholds in Rats
No full textabstract: Background:
Use of synthetic cathinones, which are designer stimulants found in “bath salts,” has increased dramatically in recent years. Following governmental bans of methylenedioxypyrovalerone, mephedrone, and methylone, a second generation of synthetic cathinones with unknown abuse liability has emerged as replacements.
Methods:
Using a discrete trials current intensity threshold intracranial self-stimulation procedure, the present study assessed the effects of 2 common second-generation synthetic cathinones, α‐pyrrolidinopentiophenone (0.1–5mg/kg) and 4-methyl-N-ethcathinone (1–100mg/kg) on brain reward function. Methamphetamine (0.1–3mg/kg) was also tested for comparison purposes.
Results:
Results revealed both α‐pyrrolidinopentiophenone and 4-methyl-N-ethcathinone produced significant intracranial self-stimulation threshold reductions similar to that of methamphetamine. α‐Pyrrolidinopentiophenone (1mg/kg) produced a significant maximal reduction in intracranial self-stimulation thresholds (~19%) most similar to maximal reductions produced by methamphetamine (1mg/kg, ~20%). Maximal reductions in intracranial self-stimulation thresholds produced by 4-methyl-N-ethcathinone were observed at 30mg/kg (~15%) and were comparable with those observed with methamphetamine and α‐pyrrolidinopentiophenone tested at the 0.3-mg/kg dose (~14%). Additional analysis of the ED50 values from log-transformed data revealed the rank order potency of these drugs as methamphetamine ≈ α‐pyrrolidinopentiophenone>4-methyl-N-ethcathinone.
Conclusions:
These data suggest that the newer second-generation synthetic cathinones activate the brain reward circuitry and thus may possess a similar degree of abuse potential as prototypical illicit psychostimulants such as methamphetamine as well as the first generation synthetic cathinone methylenedioxypyrovalerone, as previously reported.The final version of this article, as published in International Journal of Neuropsychopharmacology, can be viewed online at: https://academic.oup.com/ijnp/article-lookup/doi/10.1093/ijnp/pyu01
Identification of Eight Synthetic Cannabinoids, Including 5F-AKB48 in Seized Herbal Products Using DART-TOF-MS and LC-QTOF-MS as Nontargeted Screening Methods
No full text
Analysis of Synthetic Cannabinoids Using High-Resolution Mass Spectrometry and Mass Defect Filtering: Implications for Nontargeted Screening of Designer Drugs
No full textDetection of new designer drugs remains an analytical
challenge
because of the ability of manufacturers to rapidly substitute closely
related analogs for banned substances. Traditional targeted mass spectrometry
methods rely on library searches, known masses, or multiple reaction
monitoring (MRM) transitions and are therefore often unable to detect
or identify recently discovered or yet unreported designer drug analogs.
Here, high-resolution mass spectrometry in conjunction with mass defect
filtering is presented as a method for nontargeted analysis to detect
both known and novel analogs of designer drugs. The technique is applied
in depth to a family of designer drugs composed of indole-derived
synthetic cannabinoids closely related to JWH-018, a substance recently
controlled in the United States. A single mass defect filter with
a 50 mDa window encompasses over 80% of all currently published structures
in this family. Searching for precursor ions of common fragment ions
enables detection of compounds with mass defects that fall outside
the range of mass defect filter parameters. Application of a mass
defect filter to fragment ions prior to precursor ion searching increases
the breadth of analogs that can be detected. The combined approach
defines a broad-spectrum search for related molecules
Supramolecular Modification of Ion Chemistry: Modulation of Peptide Charge State and Dissociation Behavior through Complexation with Cucurbit[<i>n</i>]uril (<i>n</i> = 5, 6) or α-Cyclodextrin
No full textElectrospray Fourier transform ion cyclotron resonance mass spectrometry, ion mobility spectrometry, and computational methods were utilized to characterize the complexes between lysine or pentalysine with three prototypical host molecules: α-cyclodextrin (α-CD), cucurbit[5]uril (CB[5]), and cucurbit[6]uril (CB[6]). Ion mobility measurements show lysine forms externally bound, singly charged complexes with either α-CD or CB[5], but a doubly charged complex with the lysine side chain threaded through the host cavity of CB[6]. These structural differences result in distinct dissociation behaviors in collision-induced dissociation (CID) experiments: the α-CD complex dissociates via the simple loss of intact lysine, whereas the CB[5] complex dissociates to yield [CB[5] + H3O]+, and the CB[6] complex loses neutral NH3 and CO, the product ion remaining a doubly charged complex. These results are consistent with B3LYP/6−31G* binding energies (kJ mol−1) of D(Lys + H+−α−CD) = 281, D(Lys + H+−CB[5]) = 327, and D(Lys + 2H2+−CB[6]) = 600. B3LYP/6−31G* geometry optimizations show complexation with α-CD stabilizes the salt bridge form of protonated lysine, whereas complexation with CB[6] stabilizes doubly protonated lysine. Complexation of the larger polypeptide pentalysine with α-CD forms a nonspecific adduct: no modification of the pentalysine charge state distribution is observed, and dissociation occurs via the simple loss of α-CD. Complexation of pentalysine with the cucurbiturils is more specific: the observed charge state distribution shifts higher on complexation, and fragmentation patterns are significantly altered relative to uncomplexed pentalysine: C-terminal fragment ions appear that are consistent with charge stabilization by the cucurbiturils, and the cucurbiturils are retained on the fragment ions. Molecular mechanics calculations suggest CB[5] binds to two protonated sites on pentalysine without threading onto the peptide and that CB[6] binds two adjacent protonated sites via threading onto the peptide
Characterization of phosphorylated peptides using traveling wave-based and drift cell ion mobility mass spectrometry
No full textPhosphorylation is one the most studied and important post translational modifications. Nano electrospray mass spectrometry coupled with traveling wave (T-Wave)-based ion mobility has been used to filter for phosphorylated peptides in tryptic protein digests. T-Wave parameters have been optimized to maximize the separation between phosphorylated and non-phosphorylated peptides. A method to calibrate the T-Wave device, to provide estimates of collision cross sections, is presented, and these estimates are in excellent agreement with values obtained on drift cell instrumentation. Phosphorylated peptides have smaller cross sections which enables their separation from non-phosphorylated peptides of the same m/z. Post-mobility fragmentation is used to obtain the primary sequence for peptides of interest. This approach is shown to have potential as an additional screen for phosphorylated peptides, where up to 40% of observed peptides can be eliminated from the study
The effect of calcium ions and peptide ligands on the relative stabilities of the calmodulin dumbbell and compact structures
No full textA combination of ion mobility and mass spectrometry methods was used to characterize the molecular shape of the protein calmodulin (CaM) and its complexes with calcium and a number of peptide ligands. CaM, a calcium-binding protein composed of 148 amino acid residues, was found by X-ray crystallography to occur both in a globular shape and in the shape of an extended dumbbell. Here, it was found, as solutions of Cam and Cam complexes were sprayed into the solvent-free environment of the mass spectrometer, that major structural feature,., of the molecule and the stoichiometry of the units constituting a complex in Solution were preserved in the desolvation process. Two types of Cam structures were observed in Our experiments: a compact and all extended form of Cam with measured cross sections in near-perfect agreement with those calculated for the known globular and extended dumbbell X-ray geometries. Calcium-free Solutions yielded predominantly all extended Cam conformation. Ca-n(2+)-CaM complexes were observed in Calcium-containing solutions, n = 0-4, with the population of the compact conformation increasing relative to the elongated conformation as n increases. For n = 4, a predominantly compact globular conformation was observed. Solutions containing the peptide CaMKII290-309, the CaM target domain of the Ca2+/Calmodulin-dependent protein kinase II (CaMKII) enzyme, yielded predominantly globular Ca-4(2+)-CaM-CaMKII290-309 complexes. Similar results were obtained with the 26-residue peptide melittin. For the 14-residue C-terminal melittin fragment, oil the other hand, formation of both a 1: 1 and a 1:2 CaM-peptide complex was detected. Oil the basis of the entirety of our results, we Conclude that the collapse of extended (dumbbell-like) CaM structures into more compact globular Structures Occurs upon specific binding Of four calcium ions. Furthermore, this calcium-induced structural Collapse of Cam appears to be a prerequisite for formation of a particularly stable CaM-peptide complex involving peptides long enough to be engaged in interactions with both lobes of CaM
