-
Journal of Pharmaceutical and... Mar 2018Phenethylamines (PEAs) are popular substances found in weight-loss and sports nutrition supplements. They are generally pharmacologically active and primarily affect the...
Phenethylamines (PEAs) are popular substances found in weight-loss and sports nutrition supplements. They are generally pharmacologically active and primarily affect the sympathetic nervous system. Many PEAs are synthetic chemicals and are on the prohibited list of the World Anti-Doping Agency. In this study, nuclear magnetic resonance (NMR) spectroscopy was applied to detect and identify the presence of PEAs in sports dietary supplements without the need for chromatographic separation or pre-knowledge on formulation. Eight PEAs, viz. phenethylamine, synephrine, oxilofrine, hordenine, β-methylphenethylamine, N-methyltyramine, octopamine and deterenol, were identified from 32 dietary supplements sold in the US market. Furthermore, a quantitative NMR method was developed and validated for simultaneous determination of the concentrations of the PEAs. The study demonstrated that NMR could be a potential tool to monitor and detect PEAs or other ingredients in dietary supplements.
Topics: Deuterium; Diosgenin; Doping in Sports; Humans; Performance-Enhancing Substances; Phenethylamines; Phytosterols; Proton Magnetic Resonance Spectroscopy; Staining and Labeling
PubMed: 29413984
DOI: 10.1016/j.jpba.2018.01.025 -
Journal of Electrocardiology 2017Using BRAVO algorithm (AMPS-LLC, NY, v4.4.0), 5223 ECGs from a publicly available annotated dataset from a randomized clinical trial on four different compounds and...
Using BRAVO algorithm (AMPS-LLC, NY, v4.4.0), 5223 ECGs from a publicly available annotated dataset from a randomized clinical trial on four different compounds and placebo were analyzed. ECGs were automatically processed and JTp interval was computed on: 12 standard ECG leads, Vector Magnitude (VM), and root mean square (RMS) leads. On VM and RMS, JTp intervals were nearly identical (228 ± 29 vs. 227 ± 30 ms respectively, with correlation of 0.99, p < 0.0001). On lead II, JTp interval was about 10 ms longer, but highly correlated with that measured on VM (0.94, p < 0.0001). Similarly, on lead V5, JTp was about 8 ms longer than on VM, with a correlation of 0.95, p < 0.0001. When compared to the public available annotations, JTp by BRAVO generated longer (about 8 ms) measurement and evidenced outliers conducible to both the T-wave peak (in few ECGs presenting notched shapes) and, to a lesser degree, to the J point, due to variability of the two algorithms. Differences on the drug-induced effect from the four compounds were negligible.
Topics: Algorithms; Diagnosis, Computer-Assisted; Electrocardiography, Ambulatory; Heart Conduction System; Humans; Phenethylamines; Potassium Channel Blockers; Quinidine; Randomized Controlled Trials as Topic; Ranolazine; Sodium Channel Blockers; Software; Sulfonamides; Verapamil
PubMed: 28826858
DOI: 10.1016/j.jelectrocard.2017.07.010 -
Indian Heart Journal 2014Dofetilide is an effective antiarrhythmic agent for conversion of atrial fibrillation and atrial flutter as well as maintenance of sinus rhythm in appropriately selected... (Review)
Review
Dofetilide is an effective antiarrhythmic agent for conversion of atrial fibrillation and atrial flutter as well as maintenance of sinus rhythm in appropriately selected patients. However, as with other antiarrhythmic agents, proarrhythmia is a known adverse effect. The risk of dofetilide induced torsade de pointes (Tdp) is low when used with strict dosing criteria guided by renal function, QT interval and concomitant drug therapy. Benefit from dofetilide use must be individualized and weighed against the side effects and the role of other available treatment options. In this review, we discuss the underlying mechanism, risk factors and precautionary measures to avoid dofetilide induced QT prolongation and ventricular tachycardia/Tdp. We suggest a scheme for the management of QT prolongation, ventricular arrhythmia and Tdp as well.
Topics: Anti-Arrhythmia Agents; Electrocardiography; Humans; Phenethylamines; Risk Factors; Sulfonamides; Torsades de Pointes
PubMed: 25634399
DOI: 10.1016/j.ihj.2013.12.021 -
European Journal of Pharmacology Sep 2019Preworkout supplements ("boosters") are used to enhance physical and mental performance during workouts. These products may contain various chemical substances with...
Preworkout supplements ("boosters") are used to enhance physical and mental performance during workouts. These products may contain various chemical substances with undefined pharmacological activity. We investigated whether substances that are contained in commercially available athletic multiple-ingredient preworkout supplements exert amphetamine-type activity at norepinephrine, dopamine, and serotonin transporters (NET, DAT, and SERT, respectively). We assessed the in vitro monoamine transporter inhibition potencies of the substances using human embryonic kidney 293 cells that expressed the human NET, DAT, and SERT. The phenethylamines β-phenethylamine, N-methylphenethylamine, β-methylphenethylamine, N-benzylphenethylamine, N-methyl-β-methylphenethylamine, and methylsynephrine inhibited the NET and less potently the DAT similarly to D-amphetamine. β-phenethylamine was the most potent, with IC values of 0.05 and 1.8 μM at the NET and DAT, respectively. These IC values were comparable to D-amphetamine (IC = 0.09 and 1.3 μM, respectively). The alkylamines 1,3-dimethylbutylamine and 1,3-dimethylamylamine blocked the NET but not the DAT. Most of the phenethylamines interacted with trace amine-associated receptor 1, serotonin 5-hydroxytryptamine-1A receptor, and adrenergic α and α receptors at submicromolar concentrations. None of the compounds blocked the SERT. In conclusion, products that are used by athletes may contain substances with mainly noradrenergic amphetamine-type properties.
Topics: Biogenic Monoamines; Biological Transport; Catecholamine Plasma Membrane Transport Proteins; Dietary Supplements; Exercise; HEK293 Cells; Humans; Performance-Enhancing Substances; Phenethylamines
PubMed: 31265842
DOI: 10.1016/j.ejphar.2019.172515 -
ACS Chemical Neuroscience Aug 2023Serotonergic psychedelics are described to have activation of the serotonin 2A receptor (5-HT) as their main pharmacological action. Despite their relevance, the...
Serotonergic psychedelics are described to have activation of the serotonin 2A receptor (5-HT) as their main pharmacological action. Despite their relevance, the molecular mechanisms underlying the psychedelic effects induced by certain 5-HT agonists remain elusive. One of the proposed hypotheses is the occurrence of biased agonism, defined as the preferential activation of certain signaling pathways over others. This study comparatively monitored the efficiency of a diverse panel of 4-position-substituted (and -benzyl-derived) phenylalkylamines to induce recruitment of β-arrestin2 (βarr2) or miniGα to the 5-HT, allowing us to assess structure-activity relationships and biased agonism. All test compounds exhibited agonist properties with a relatively large range of both EC and values. Interestingly, the lipophilicity of the 2C-X phenethylamines was correlated with their efficacy in both assays but yielded a stronger correlation in the miniGα- than in the βarr2-assay. Molecular docking suggested that accommodation of the 4-substituent of the 2C-X analogues in a hydrophobic pocket between transmembrane helices 4 and 5 of 5-HT may contribute to this differential effect. Aside from previously used standard conditions (lysergic acid diethylamide (LSD) as a reference agonist and a 2 h activation profile to assess a compound's activity), serotonin was included as a second reference agonist, and the compounds' activities were also assessed using the first 30 min of the activation profile. Under all assessed circumstances, the qualitative structure-activity relationships remained unchanged. Furthermore, the use of two reference agonists allowed for the estimation of both "benchmark bias" (relative to LSD) and "physiology bias" (relative to serotonin).
Topics: Serotonin; Receptor, Serotonin, 5-HT2A; Molecular Docking Simulation; Hallucinogens; Phenethylamines; Serotonin 5-HT2 Receptor Agonists
PubMed: 37474114
DOI: 10.1021/acschemneuro.3c00267 -
Drug and Chemical Toxicology Jan 2015Substituted phenethylamines are a class of designer drugs that have recently emerged in the drug abuse market. Such substances remain legal to use, possess, and supply... (Review)
Review
Substituted phenethylamines are a class of designer drugs that have recently emerged in the drug abuse market. Such substances remain legal to use, possess, and supply until these compounds become classified as scheduled. 2C-I-NBOMe or 25I-NBOMe is the N-benzyl-derivative of the iodo-substituted dimethoxy-phenethylamine (2C-I) that appeared recently in the drug market under the street name "N-Bomb". Due to its high potency, intoxications and fatal cases related to 2C-I-NBOMe use are increased worldwide. The use and trafficking of this substituted phenethylamine is banned only in some countries. A comprehensive review was performed using PubMed and Medline databases, together with additional non-peer reviewed information sources, including books and publications of state authorities in different countries, regarding chemistry, availability, pharmacology, and toxicology of 2C-I-NBOMe. Intoxications or lethal cases, published or reported, as well as the current legislation on this newly introduced drug are also reviewed.
Topics: Designer Drugs; Dimethoxyphenylethylamine; Drug and Narcotic Control; Humans; Molecular Structure; Substance Abuse Detection; Substance-Related Disorders
PubMed: 24785196
DOI: 10.3109/01480545.2014.911882 -
Molecular Psychiatry Nov 2016Deprenyl/Selegiline (DEP), created by Joseph Knoll in the 1960s, registered in more than 60 countries to treat Parkinson's disease, Alzheimer's disease, major depressive... (Review)
Review
Deprenyl/Selegiline (DEP), created by Joseph Knoll in the 1960s, registered in more than 60 countries to treat Parkinson's disease, Alzheimer's disease, major depressive disorder; and used as an anti-aging drug, achieved its place in research and therapy as the first selective inhibitor of B-type monoamine oxidase (MAO-B). The demonstration that the DEP analog (-)-1-phenyl-2-propylaminopentane devoid of MAO inhibitory property, enhanced like DEP the activity of the catecholaminergic brain engine revealed that this effect is unrelated to the selective inhibition of MAO-B. β-Phenylethylamine (PEA), the important trace-amine in the mammalian brain, is known to be a releaser of catecholamines. Amphetamine and methamphetamine, the best known synthetic PEA derivatives are also releasers of catecholamines like their parent compound. DEP is a unique synthetic PEA derivative devoid of the catecholamine releasing property. As the releasing effect conceals the catecholaminergic activity enhancer (CAE) effect, it remained undiscovered until DEP uncovered that PEA is a natural CAE substance; and only releases catecholamines in high concentration. Discovering that tryptamine is a natural enhancer of catecholaminergic and serotonergic neurons catalyzed the development of R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane (BPAP); the most potent and selective enhancer substance, and it exerts its enhancer effect in 0.0001 mg kg. DEP and BPAP initiated an analysis of the enhancer regulation in the mammalian brain. Studies regarding the nature of the enhancer regulation revealed that this regulation is enhanced after weaning and sex hormones return it to the pre-weaning level. Thus, sex hormones elicit the transition of the developmental phase of life into the post-developmental, downhill (aging) period. The aging-related, slow decline in the enhancer regulation of the catecholaminergic brain engine, the main activator of the cortex, is the prime factor of brain aging. The enhancer regulation's decay in the most rapidly aging dopaminergic system is, for example, mainly responsible for the decline in learning ability and sexual activity over time. According to the Knoll concept, based on two longevity studies performed on male rats, to keep the catecholaminergic brain engine, from the beginning of the downhill period of life, via the administration of a small daily dose of a CAE substance (presently DEP is the only available drug) on a higher activity level, thus to fight against the physiological aging-related slow decay of the catecholaminergic system, is a suitable anti-aging therapy. As our present knowledge regarding the enhancer regulation in the mammalian brain is like seeing a peak of an iceberg, the future of this new line of brain research looks promising from both theoretical and practical aspects.
Topics: Aging; Alzheimer Disease; Animals; Brain; Catecholamines; Depressive Disorder, Major; Dopamine; History, 20th Century; Humans; Monoamine Oxidase; Parkinson Disease; Phenethylamines; Rats; Selegiline
PubMed: 27480491
DOI: 10.1038/mp.2016.127 -
Circulation. Arrhythmia and... Oct 2017
Topics: Arrhythmias, Cardiac; Humans; Phenethylamines; Sulfonamides
PubMed: 29038110
DOI: 10.1161/CIRCEP.117.005815 -
Forensic Science International Oct 2017A teenager male was found dead in a waterway after he was spotted jumping off into the water stream. The boy looked agitated and confused after a party with friends. At...
A teenager male was found dead in a waterway after he was spotted jumping off into the water stream. The boy looked agitated and confused after a party with friends. At the gathering place, investigators seized packages of blotter papers. A complete autopsy and a histological evaluation of the main tissues were performed; although the death occurred by drowning, the prosecutor requested toxicological exams, in order to evaluate the potential role of drugs of abuse in the episode. Blood (both peripheral and central) and urine samples as well as seized blotter papers were collected and analyzed as follows. The blotter paper, analyzed through a GC-MS method, revealed the presence of 25-NBOMes. A liquid chromatography tandem mass spectrometric (LC-MS/MS) system was used to identify and quantify 5 different 25-NBOMes (namely 25B-NBOMe, 25C-NBOMe, 25D-NBOMe, 25H-NBOMe, 25I-NBOMe) in blood and urine. 25E-NBOMe was used as internal standard (IS). 1mL of urine and 1mL of blood (both peripheral and cardiac) were diluted in 2mL phosphate buffer at pH 6.0, containing IS and purified on a solid phase extraction (SPE) cartridge. LOD and LOQ for the five 25-NBOMes were calculated at 0.05 and 0.1ng/mL respectively. Linearity, accuracy, precision, ion suppression, carry over and recovery were tested and all parameters fulfilled the acceptance criteria. Blood and urine provided positive results for 25C-NBOMe and 25H-NBOMe. Eventually, the seized blotter papers were analyzed by means of LC-MS/MS and the presence of the two NBOMes was confirmed: 25C-NBOMe and 25H-NBOMe were measured at the concentration of 2.80 and 0.29ng/mL in peripheral blood, of 1.43 and 0.13ng/mL in central blood and of 0.94 and 0.14ng/mL in urine, respectively. THC and THCCOOH were also detected in biological fluids, at the concentration of 15.5 and 56.0ng/mL in peripheral blood, 9.9 and 8.5ng/mL in central blood, respectively. NBOMes can produce severe hallucination even at very low doses, and the 25C-NBOMe levels measured in the subject's blood are considered potentially toxic.
Topics: Administration, Sublingual; Adolescent; Benzylamines; Chromatography, Liquid; Drowning; Gas Chromatography-Mass Spectrometry; Hallucinogens; Humans; Male; Phenethylamines; Substance-Related Disorders
PubMed: 28893436
DOI: 10.1016/j.forsciint.2017.08.028 -
Annual International Conference of the... Jul 2019Dofetilide is an antiarrhythmic drug that selectively inhibits the rapid component of the delayed rectifier potassium current. The administration of dofetilide may cause...
Dofetilide is an antiarrhythmic drug that selectively inhibits the rapid component of the delayed rectifier potassium current. The administration of dofetilide may cause ventricular arrhythmias and torsade de pointes. Electrocardiographic (ECG) microvolt T-wave alternans (TWA), an electrophysiologic phenomenon consisting in the beat-to-beat alternation of the T-wave amplitude requiring computerized algorithms to be detected, has also been associated to malignant ventricular arrhythmias. Aim of the present study was to evaluate if dofetilide induces TWA during the 24 hours following administration. The study population consisted of 22 healthy subjects ("ECG Effects of Ranolazine, Dofetilide, Verapamil, and Quinidine in Healthy Subjects" database by Physionet) to whom a 500 μg-dose of dofetilide was administered. For each subject, 10 s ECG were acquired at baseline (0.5 hour before dofetilide administration) and at 15 time points during the 24 hours following the drug administration. ECG were then processed for automatic TWA detection by correlation method. In 21 subjects out of 22, after dofetilide administration, TWA significantly increased to a peak value (median TWA values went from 6 μV at baseline to a max 32 μV; p<; 0.05), on average after 5 hours, to then come back to values closer to baseline. Thus, in healthy subjects, dofetilide increases occurrence and levels (6 times baseline value on average) of TWA in the hours following its administration.
Topics: Arrhythmias, Cardiac; Electrocardiography; Humans; Phenethylamines; Sulfonamides
PubMed: 31945853
DOI: 10.1109/EMBC.2019.8857486