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Circulation Research Apr 2020Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT...
RATIONALE
Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT interval is too sensitive a marker and not selective, resulting in many useful drugs eliminated in drug discovery.
OBJECTIVE
To predict the impact of a drug from the drug chemistry on the cardiac rhythm.
METHODS AND RESULTS
In a new linkage, we connected atomistic scale information to protein, cell, and tissue scales by predicting drug-binding affinities and rates from simulation of ion channel and drug structure interactions and then used these values to model drug effects on the hERG channel. Model components were integrated into predictive models at the cell and tissue scales to expose fundamental arrhythmia vulnerability mechanisms and complex interactions underlying emergent behaviors. Human clinical data were used for model framework validation and showed excellent agreement, demonstrating feasibility of a new approach for cardiotoxicity prediction.
CONCLUSIONS
We present a multiscale model framework to predict electrotoxicity in the heart from the atom to the rhythm. Novel mechanistic insights emerged at all scales of the system, from the specific nature of proarrhythmic drug interaction with the hERG channel, to the fundamental cellular and tissue-level arrhythmia mechanisms. Applications of machine learning indicate necessary and sufficient parameters that predict arrhythmia vulnerability. We expect that the model framework may be expanded to make an impact in drug discovery, drug safety screening for a variety of compounds and targets, and in a variety of regulatory processes.
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiotoxicity; Cardiotoxins; Computer Simulation; Drug Discovery; ERG1 Potassium Channel; Female; Humans; Long QT Syndrome; Machine Learning; Male; Moxifloxacin; Myocytes, Cardiac; Phenethylamines; Protein Structure, Secondary; Sulfonamides; Topoisomerase II Inhibitors
PubMed: 32091972
DOI: 10.1161/CIRCRESAHA.119.316404 -
Scientific Reports Sep 2023Natural phenethylamines are trace amine neurotransmitters associated with dopamine transmission and related illnesses such Parkinson's disease, and addiction. Synthetic...
A molecular analysis of substituted phenylethylamines as potential microtubule targeting agents through in silico methods and in vitro microtubule-polymerization activity.
Natural phenethylamines are trace amine neurotransmitters associated with dopamine transmission and related illnesses such Parkinson's disease, and addiction. Synthetic phenethylamines can have psychoactive and hallucinogenic effects due to their high affinity with the 5-HT receptor. Evidence indicates phenethylamines can directly alter the microtubule cytoskeleton being structurally similar to the microtubule destabilizing agent colchicine, however little work has been done on this interaction. As microtubules provide neuron structure, intracellular transport, and influence synaptic plasticity the interaction of phenethylamines with microtubules is important for understanding the potential harms, or potential pharmaceutical use of phenethylamines. We investigated 110 phenethylamines and their interaction with microtubules. Here we performed molecular docking of these compounds at the colchicine binding site and ranked them via binding energy. The top 10% of phenethylamines were further screened based on pharmacokinetic and physicochemical properties derived from SwissADME and LightBBB. Based on these properties 25B-NBF, 25C-NBF, and DMBMPP were tested in in vitro microtubule polymerization assays showing that they alter microtubule polymerization dynamics in a dose dependent manner. As these compounds can rapidly cross the blood brain barrier and directly affect cytoskeletal dynamics, they have the potential to modulate cytoskeletal based neural plasticity. Further investigations into these mechanisms are warranted.
Topics: Phenethylamines; Molecular Docking Simulation; Polymerization; Microtubules; Colchicine
PubMed: 37658096
DOI: 10.1038/s41598-023-41600-9 -
The Plant Journal : For Cell and... Nov 2023
Topics: Mescaline
PubMed: 37861456
DOI: 10.1111/tpj.16503 -
Occurrence and Transformation of Ephedrine/Pseudoephedrine and Methcathinone in Wastewater in China.Environmental Science & Technology Jul 2022Previous wastewater-based epidemiology studies on methcathinone (MC), a controlled substance in many countries, attributed its occurrence in wastewater to its misuse....
Previous wastewater-based epidemiology studies on methcathinone (MC), a controlled substance in many countries, attributed its occurrence in wastewater to its misuse. However, such attribution did not consider the possibility that MC may also come from the transformation of ephedrine (EPH) and pseudo-ephedrine (PEPH). In this work, EPH/PEPH and MC in wastewater of six major Chinese cities were systematically examined. EPH/PEPH concentrations in all the cities showed clear seasonal variations, with maximum and minimum concentrations observed in winter and summer, respectively. In contrast, MC concentrations were the lowest in winter, leading to minimum concentration ratios between MC and EPH/PEPH in winter. Lack of MC seizure in the cities suggests that MC abuse could not account for the ubiquitous detection of the substance in the wastewater of these cities. Batch experiments confirmed EPH/PEPH transformation into MC in wastewater. The significantly lower transformation rate at a lower temperature was consistent with low MC concentrations in winter. These results indicate that when monitoring MC through wastewater, EPH/PEPH concentrations must be determined simultaneously to avoid false identification of MC abuse. The observed ratios of MC to EPH/PEPH concentrations in this work may be used to determine MC abuse. Alternatively, other biomarkers (e.g., cathinone) may be considered to avoid interference from EPH/PEPH transformation.
Topics: Ephedrine; Propiophenones; Pseudoephedrine; Wastewater
PubMed: 35793412
DOI: 10.1021/acs.est.2c02639 -
Fa Yi Xue Za Zhi Feb 2024To investigate the toxicokinetic differences of 3,4-methylenedioxy--methylamphetamine (MDMA) and its metabolite 4,5-methylene dioxy amphetamine (MDA) in rats after...
OBJECTIVES
To investigate the toxicokinetic differences of 3,4-methylenedioxy--methylamphetamine (MDMA) and its metabolite 4,5-methylene dioxy amphetamine (MDA) in rats after single and continuous administration of MDMA, providing reference data for the forensic identification of MDMA.
METHODS
A total of 24 rats in the single administration group were randomly divided into 5, 10 and 20 mg/kg experimental groups and the control group, with 6 rats in each group. The experimental group was given intraperitoneal injection of MDMA, and the control group was given intraperitoneal injection of the same volume of normal saline as the experimental group. The amount of 0.5 mL blood was collected from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. In the continuous administration group, 24 rats were randomly divided into the experimental group (18 rats) and the control group (6 rats). The experimental group was given MDMA 7 d by continuous intraperitoneal injection in increments of 5, 7, 9, 11, 13, 15, 17 mg/kg per day, respectively, while the control group was given the same volume of normal saline as the experimental group by intraperitoneal injection. On the eighth day, the experimental rats were randomly divided into 5, 10 and 20 mg/kg dose groups, with 6 rats in each group. MDMA was injected intraperitoneally, and the control group was injected intraperitoneally with the same volume of normal saline as the experimental group. On the eighth day, 0.5 mL of blood was taken from the medial canthus 5 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h after administration. Liquid chromatography-triple quadrupole tandem mass spectrometry was used to detect MDMA and MDA levels, and statistical software was employed for data analysis.
RESULTS
In the single-administration group, peak concentrations of MDMA and MDA were reached at 5 min and 1 h after administration, respectively, with the largest detection time limit of 12 h. In the continuous administration group, peak concentrations were reached at 30 min and 1.5 h after administration, respectively, with the largest detection time limit of 10 h. Nonlinear fitting equations for the concentration ratio of MDMA and MDA in plasma and administration time in the single-administration group and continuous administration group were as follows: =10.362, =0.974 6; =7.397 3, =0.961 5 (: injection time; : concentration ratio of MDMA to MDA in plasma).
CONCLUSIONS
The toxicokinetic data of MDMA and its metabolite MDA in rats, obtained through single and continuous administration, including peak concentration, peak time, detection time limit, and the relationship between concentration ratio and administration time, provide a theoretical and data foundation for relevant forensic identification.
Topics: Rats; Animals; Amphetamine; N-Methyl-3,4-methylenedioxyamphetamine; 3,4-Methylenedioxyamphetamine; Toxicokinetics; Saline Solution; Amphetamines
PubMed: 38500459
DOI: 10.12116/j.issn.1004-5619.2022.320201 -
Behavioural Pharmacology Oct 2021Depression and anxiety are common neuropsychiatric disorders that usually appear as comorbidities. The development of new drugs is crucial for safer and more effective...
Depression and anxiety are common neuropsychiatric disorders that usually appear as comorbidities. The development of new drugs is crucial for safer and more effective clinical management of both disorders. Riparin A is a synthetic chemical analog of riparins that naturally occur in several medicinal plants. Marked pharmacological effects such as anxiolytic and antidepressant properties characterize this class of compounds. However, little is known about the potential anxiolytic and antidepressant effects of Riparin A. In this work, we showed that, unlike other riparins, Riparin A exerts only a very mild anxiolytic-like effect as demonstrated by the results of classical behavioral tests such as the elevated plus-maze, light-dark box and open-field tests in rats. However, all doses of Riparin A (2.5; 5.0 and 10 mg/kg; intraperitoneal) have shown significant antidepressant activity in rats submitted to forced swimming test. In addition to this interesting pharmacological property, Riparin A did not promote any important alterations in the locomotor performance of the animals as specifically demonstrated by the rotarod test. Furthermore, Riparin A did not induce sedation in treated animals; instead, this compound appears to increase the animal's state of alertness as measured by the latency time to loss of reflexes and time to recovery from sleep in rats submitted to the pentobarbital-induced sleep time test. The present results point to an antidepressant effect of Riparin A and reinforce the pharmaceutical interest in the group of riparins, particularly their high potential for use in new studies investigating the structure-activity relationships between member compounds.
Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Behavior, Animal; Benzamides; Depression; Disease Models, Animal; Drug Monitoring; Mice; Phenethylamines; Rats; Rotarod Performance Test; Sleep; Treatment Outcome
PubMed: 34483245
DOI: 10.1097/FBP.0000000000000654 -
Drug and Chemical Toxicology Jul 2020Phenylethylamine's acute toxic effects in a population of adult (10 to 12 weeks old; ∼30 g) Swiss male albino mice are significantly increased by para-position...
Phenylethylamine's acute toxic effects in a population of adult (10 to 12 weeks old; ∼30 g) Swiss male albino mice are significantly increased by para-position aromatic ring halogenation. LD, LD, and LD values (mg/kg; x ± SEM) for p-F- (116.7 ± 3.3, 136.7 ± 1.7, and 160.0 ± 2.9), p-Br- (126.7 ± 3.3, 145.0 ± 2.9, and 163.3 ± 3.3), p-Cl- (133.3 ± 3.3, 146.7 ± 1.7, and 165.0 ± 2.9), and p-I-PEA (133.3 ± 3.3, 153.3 ± 1.7, and 168.3 ± 1.7), compared to PEA 203.3 ± 3.3, 226.7 ± 4.4, and 258.3 ± 8.8). Like PEA, the difference between LD and LD, and LD and LD for individual amines were similar and in the range (10 to 20%). Toxicity variation between the various p-halogenatedPEAs also fell within a relatively narrow range (as a group: LD 116.7 ± 3.3 to 133.3 ± 3.3, LD 136.7 ± 1.7 to 153.3 ± 1.7, and LD 160.0 ± 2.9 to 168.3 ± 1.7 mg/kg). PEA methylation, (exception of its α-methyl derivative), results in relatively modest changes in acute toxicity. LD, LD, and LD values (mg/kg; x ± SEM) for N-Me- (176.6 ± 3.3, 200.0 ± 2.9, and 221.7 ± 3.3), p-Me- (183.3 ± 3.3, 206.7 ± 3.3, and 225.0 ± 2.9), o-Me- (210.0 ± 5.8, 233.3 ± 3.3, and 258.3 ± 1.7), and β-MePEA (220.0 ± 5.8, 243.3 ± 4.4, and 278.3 ± 44). Similar to PEA, and the p-HPEAs, the difference between LD and LD and LD and LD values for individual amines fell within a relatively narrow range (10 to 20%). Variation in toxicity among the methylatedPEAs also fell within a limited range (as a group: LD 176 ± 3.3 to 220 ± 5.8, LD 200.0 ± 2.9 to 243.3 ± 4.4 and LD 221.7 ± 3.3 to 278.3 ± 4.4 mg/kg). With the exception of PEA's methyl derivative (amphetamine) all the amines studied are rapidly metabolized by monoamine oxidase. This pharmacokinetics difference would help to explain the markedly higher amphetamine toxicity [(LD, LD and LD (mg/kg; x ± SEM) of 21.3 ± 0.9, 25.0 ± 0.6, and 29.3 ± 0.7, respectively)].
Topics: Animals; Lethal Dose 50; Male; Mice; Phenethylamines; Toxicity Tests, Acute
PubMed: 30614291
DOI: 10.1080/01480545.2018.1551899 -
Gaceta Medica de Mexico 2021Estrogens that are used as contraceptives or in replacement therapy are associated with an increase in the risk for developing thrombosis, mainly during the first year...
BACKGROUND
Estrogens that are used as contraceptives or in replacement therapy are associated with an increase in the risk for developing thrombosis, mainly during the first year of treatment and in women with associated risk factors.
OBJECTIVE
To synthesize, characterize and identify the anticoagulant, antiplatelet aggregation and microvesicle-reducing effect of the new aminoestrogen Tyrame.
MATERIAL AND METHODS
CD1 strain mice were used, which had Tyrame (0, 1 and 2 mg/100 g) subcutaneously administered. At 24 h, a blood sample was obtained to determine whole-blood clotting time, microvesicles concentration and inhibitory effect on platelet aggregation.
RESULTS
Blood clotting time increased up to 1.5 times in comparison with the control. Platelet aggregation inhibition had different magnitude depending on the agonist agent employed, and was complete with collagen. Both effects had a dose-dependent relationship. The microvesicles decreased up to six times with respect to the control.
CONCLUSIONS
Tyrame reduces platelet aggregation and microvesicle formation, which emphasizes its potential therapeutic utility as an estrogen free of thrombotic effects.
Topics: Animals; Anticoagulants; Fibrinolytic Agents; Mice; Phenethylamines; Platelet Aggregation; Thrombosis
PubMed: 35108248
DOI: 10.24875/GMM.M21000621 -
Journal of Forensic Sciences Sep 2019Ephedrine (EPH) and pseudoephedrine (PSE) were studied by micro-Raman spectroscopy and UV resonance Raman spectroscopy excited at 785 and 360 nm, respectively. Raman...
Ephedrine (EPH) and pseudoephedrine (PSE) were studied by micro-Raman spectroscopy and UV resonance Raman spectroscopy excited at 785 and 360 nm, respectively. Raman bands at approximately 245 and 410 cm for ephedrine have apparent differences from the same bands at approximately 215, 265, 350, 450, and 555 cm for pseudoephedrine, and these differences can be applied to distinguish between EPH and PSE. Additionally, density functional theory was used for the Raman calculations to obtain results identical to the experimental spectra. This work is expected to expand the applications of Raman spectroscopy in forensic science.
Topics: Central Nervous System Stimulants; Density Functional Theory; Ephedrine; Humans; Molecular Structure; Pseudoephedrine; Spectrum Analysis, Raman
PubMed: 30835831
DOI: 10.1111/1556-4029.14015 -
Drug Testing and Analysis Jul 2022The group of P2P precursors including α-phenylacetoacetonitrile (APAAN), α-phenylacetoamide (APAA) and methyl α-acetylphenylacetate (MAPA) has become increasingly...
The group of P2P precursors including α-phenylacetoacetonitrile (APAAN), α-phenylacetoamide (APAA) and methyl α-acetylphenylacetate (MAPA) has become increasingly popular in Europe and other parts of the world in the last decade. Previous investigations have reported the use of APAAN in the synthesis of amphetamine and methamphetamine and identified a range of characteristic impurities. This research has expanded upon the current literature by investigating the use of MAPA in the synthesis of methamphetamine. In this study methamphetamine was synthesized via three common clandestine methods: the Leuckart synthesis and two reductive amination methods. We report the identification of seven impurities, four of which are methyl ester equivalents of impurities previously reported for the detection of APAAN. These are methyl 2-phenylbut-2-enoate, methyl 2-phenyl-3-hydroxybutanoate, methyl 3-(methylamino)-2-phenylbut-2-enoate and methyl 3-(methylamino)-2-phenylbutanoate. The other impurities identified are ethyl ester compounds formed via transesterification of the methyl ester due to the reaction solvent. This susceptibility for transesterification suggests that identification of the pre-precursor used may not always be straightforward and may be dependent on the reaction conditions employed. Of the impurities reported, methyl 3-(methylamino)-2-phenylbutanoate was deemed to be a potentially reliable impurity for detection of the use of MAPA; however, it is expected that lower levels of characteristic impurities may be detected in methamphetamine synthesized from MAPA than that from APAAN.
Topics: Amphetamine; Central Nervous System Stimulants; Drug Contamination; Esters; Illicit Drugs; Methamphetamine
PubMed: 35307969
DOI: 10.1002/dta.3256