-
Bioorganic Chemistry Mar 2024Due to the important biological properties of dopamine, phenethylamine, and tyramine derivatives in the central nervous system, herein the synthesis of novel α-benzyl...
Due to the important biological properties of dopamine, phenethylamine, and tyramine derivatives in the central nervous system, herein the synthesis of novel α-benzyl dopamine, phenethylamine, and tyramine derivatives is described. The title compounds were synthesized starting from 3-phenylpropanoic acids and methoxybenzenes in six or seven steps. Firstly, 3-(2,3-dimethoxyphenyl)propanoic acid (11) and 3-(3,4-dimethoxyphenyl)propanoic acid (12) were selectively brominated with N-bromosuccinimide (NBS). The Friedel-Crafts acylation of methoxylated benzenes with these brominated acids or commercially available 3-phenylpropanoic acid in polyphosphoric acid gave the desired dihydrochalcones. α-Carboxylation of dihydrochalcones, reduction of benzylic carbonyl groups, hydrolysis of esters to acid derivatives, and the Curtius rearrangement reaction of acids followed by in situ synthesis of carbamates from alkyl isocyanates and hydrogenolysis of the carbamates afforded the title compounds in good total yields. Alzheimer's disease (AD) and Parkinson's disease (PD) are chronic neurodegenerative diseases that become serious over time. However, the exact pathophysiology of both diseases has not been revealed yet. There have been many different approaches to the treatment of patients for many years, especially studies on the cholinergic system cover a wide area. Within the scope of this study, the inhibition effects of dopamine-derived carbamates and amine salts on the cholinergic enzymes AChE and BChE were examined. Dopamine-derived carbamate 24a-i showed inhibition in the micro-nanomolar range; compound 24d showed a K value of 26.79 nM against AChE and 3.33 nM against BChE, while another molecule, 24i, showed a K range of 27.24 nM and 0.92 nM against AChE and BChE, respectively. AChE and BChE were effectively inhibited by dopamine-derived amine salts 25j-s, with K values in the range of 17.70 to 468.57 µM and 0.76-211.23 µM, respectively. Additionally, 24c, 24e and 25m were determined to be 60, 276 and 90 times more selective against BChE than AChE, respectively.
Topics: Humans; Cholinesterase Inhibitors; Dopamine; Propionates; Structure-Activity Relationship; Cholinergic Antagonists; Salts; Acetylcholinesterase; Carbamates; Phenethylamines; Molecular Docking Simulation
PubMed: 38262088
DOI: 10.1016/j.bioorg.2024.107146 -
Journal of Pharmaceutical and... Aug 2019A novel method using UPLC with tandem mass-spectrometric detection (UPLC-MS/MS) with positive electrospray ionization was developed for the detection of the...
A novel method using UPLC with tandem mass-spectrometric detection (UPLC-MS/MS) with positive electrospray ionization was developed for the detection of the antiarrhythmic drug, dofetilide, in mouse plasma and urine. Protein precipitation was performed on 10 μL of plasma and 2 μL of urine samples using dofetilide-D4 as an internal standard, and separation of the analyte was accomplished on a C18 analytical column with the flow of 0.40 mL/min. Subsequently, the method was successfully applied to determine the pharmacokinetic parameters of dofetilide following oral and intravenous administration. The calibration curve was linear over the selected concentration range (R ≥ 0.99), with a lower limit of quantitation of 5 ng/mL. The intra-day and inter-day precisions, and accuracies obtained from a 5-day validation ranged from 3.00 to 7.10%, 3.80-7.20%, and 93.0-106% for plasma, and 3.50-9.00%, 3.70-10.0%, 87.0-106% for urine, while the recovery of dofetilide was 93.7% and 97.4% in plasma and urine, respectively. The observed pharmacokinetic profiles revealed that absorption is the rate-limiting step in dofetilide distribution and elimination. Pharmacokinetic studies illustrate that the absolute bioavailability of dofetilide in the FVB strain mice is 34.5%. The current developed method allows for accurate and precise quantification of dofetilide in micro-volumes of plasma and urine, and was found to be suitable for supporting in vivo pharmacokinetic studies.
Topics: Animals; Biological Availability; Body Fluids; Calibration; Chromatography, High Pressure Liquid; Limit of Detection; Male; Mice; Phenethylamines; Plasma; Sulfonamides; Tandem Mass Spectrometry
PubMed: 31055183
DOI: 10.1016/j.jpba.2019.04.041 -
European Journal of Pharmacology Sep 2023Ring-substituted phenethylamines are believed to induce psychedelic effects primarily by interacting with 5-hydroxytryptamine 2 (5-HT2A) receptors in the brain. We...
Ring-substituted phenethylamines are believed to induce psychedelic effects primarily by interacting with 5-hydroxytryptamine 2 (5-HT2A) receptors in the brain. We assessed the effect of the psychedelic substances 25H-NBOMe and 25H-NBOH on the depressive-like behavior of male adult rats. Naive Wistar rats were divided into groups to assess the effects of different doses (0.1 mg/kg, 1 mg/kg, and 3 mg/kg) of 25H-NBOMe and 25H-NBOH. The substances were administered intraperitoneally and the hallucinogenic properties were evaluated using the head twitch response test (HTR). Additionally, we assessed their locomotor activity in the open field test (OFT) and depressive-like behavior in the forced swimming test (FST). Our data demonstrated that all doses of synthetic psychedelic substances evaluated exhibited hallucinogenic effects. Interestingly, we observed that both 25H-NBOMe and 25H-NBOH produced a significantly greater motivation to escape in the FST, compared to the control group. Furthermore, we found no significant differences in locomotor activity during the OFT, except for the dose of 3 mg/kg, which induced a reduction in locomotion. This study provides new insights into a potential psychedelic substance, specifically by demonstrating the previously unknown antidepressant properties of a single dose of both 25H-NBOMe and 25H-NBOH. These findings contribute to the ongoing progress of experimental psychiatry toward developing safe and effective clinical practices in the field of psychedelics research.
Topics: Rats; Male; Animals; Hallucinogens; Rats, Wistar; Antidepressive Agents; Phenethylamines; Swimming
PubMed: 37479015
DOI: 10.1016/j.ejphar.2023.175926 -
Inorganic Chemistry Feb 2021Clenbuterol (CLE) and ractopamine (RAC) are two kinds of typical β-adrenergic agonists which pose a serious threat to the health of human beings. In this work, 10 kinds...
Clenbuterol (CLE) and ractopamine (RAC) are two kinds of typical β-adrenergic agonists which pose a serious threat to the health of human beings. In this work, 10 kinds of metal-organic frameworks (MOFs) with high stability and various pore features are screened to assess adsorption performance for CLE and RAC. An Al(III)-MOF (BUT-19) with abundant ethyl groups exhibits exceptional performance in removing CLE and RAC from water. The maximum adsorption capacity for CLE and RAC are up to 294.1 and 366.3 mg/g under the optimum adsorption conditions, respectively. Meanwhile, the adsorption mechanism effects of pH, temperature, and coexisted ions are investigated systematically. It is found that the MOF pore size and weak hydrogen-bond interactions between CLE/RAC molecules and the MOF are the main causes leading to the extraordinary adsorption. This study provides a new idea for the purposeful design and synthesis of MOFs for removing environmental pollutants and sheds light on the depuration of contaminated water.
Topics: Aluminum; Clenbuterol; Metal-Organic Frameworks; Molecular Structure; Phenethylamines; Water Pollutants, Chemical
PubMed: 33444010
DOI: 10.1021/acs.inorgchem.0c03296 -
Drug Testing and Analysis Oct 2018Numerous 2,5-dimethoxy-N-benzylphenethylamines (NBOMe), carrying a variety of lipophilic substituents at the 4-position, are potent agonists at 5-hydroxytryptamine (5HT...
Numerous 2,5-dimethoxy-N-benzylphenethylamines (NBOMe), carrying a variety of lipophilic substituents at the 4-position, are potent agonists at 5-hydroxytryptamine (5HT ) receptors and show hallucinogenic effects. The present study investigated the metabolism of 25D-NBOMe, 25E-NBOMe, and 25N-NBOMe using the microsomal model of pooled human liver microsomes (pHLM) and the microbial model of the fungi Cunninghamella elegans (C. elegans). Identification of metabolites was performed using liquid chromatography-high resolution-tandem mass spectrometry (LC-HR-MS/MS) with a quadrupole time-of-flight (QqToF) instrument. In total, 36 25D-NBOMe phase I metabolites, 26 25E-NBOMe phase I metabolites and 24 25N-NBOMe phase I metabolites were detected and identified in pHLM. Furthermore, 14 metabolites of 25D-NBOMe, 11 25E-NBOMe metabolites, and nine 25N-NBOMe metabolites could be found in C. elegans. The main biotransformation steps observed were oxidative deamination, oxidative N-dealkylation also in combination with hydroxylation, oxidative O-demethylation possibly combined with hydroxylation, oxidation of secondary alcohols, mono- and dihydroxylation, oxidation of primary alcohols, and carboxylation of primary alcohols. Additionally, oxidative di-O-demethylation for 25E-NBOMe and reduction of the aromatic nitro group and N-acetylation of the primary aromatic amine for 25N-NBOMe took place. The resulting 25N-NBOMe metabolites were unique for NBOMe compounds. For all NBOMes investigated, the corresponding 2,5-dimethoxyphenethylamine (2C-X) metabolite was detected. This study reports for the first time 25X-NBOMe N-oxide metabolites and hydroxylamine metabolites, which were identified for 25D-NBOMe and 25N-NBOMe and all three investigated NBOMes, respectively. C. elegans was capable of generating all main biotransformation steps observed in pHLM and might therefore be an interesting model for further studies of new psychoactive substances (NPS) metabolism.
Topics: Biotransformation; Chromatography, Liquid; Cunninghamella; Designer Drugs; Humans; Hydroxylation; Methylation; Microsomes, Liver; Oxidation-Reduction; Phenethylamines; Psychotropic Drugs; Tandem Mass Spectrometry
PubMed: 29971945
DOI: 10.1002/dta.2446 -
Natural Product Research Sep 2022species are known edible mushrooms in Nigeria, believed to have exceptional culinary and nutraceutical properties. Methanol extract from fruiting bodies of was...
species are known edible mushrooms in Nigeria, believed to have exceptional culinary and nutraceutical properties. Methanol extract from fruiting bodies of was evaluated for antidiabetic activity using α-amylase and α-glucosidase assays. The isolation and structural elucidation of metabolites from the . extract afforded five compounds including a new natural product γ-glutamyl-β-phenylethylamine and four known phenyl derivatives: tryptophan , 4-hydroxyphenylacetic acid , 4-hydroxyphenylpropionic acid , and phenyllactic acid . Structures were elucidated from analyses of spectroscopic data (1D and 2D NMR, HRESIMS) and all isolated compounds were tested for α-amylase and α-glycosidase inhibitory activity. The assay established crude extract to possess and inhibition with IC of 78.05µg/mL and 86.10µg/mL, respectively. The isolated compounds compared favourably with the standard drug, acarbose with IC ranging from 6.18-15.08µg/mL and 18.28-44.63µg/mL for α-amylase and glucosidase, respectively.
Topics: Agaricales; Glycoside Hydrolase Inhibitors; Nigeria; Phenethylamines; Plant Extracts; Termitomyces; alpha-Amylases; alpha-Glucosidases
PubMed: 34878952
DOI: 10.1080/14786419.2021.2012774 -
Journal of Animal Science Oct 2014The study was performed to evaluate the effect of feeding ractopamine (RAC) to physically castrated barrows (PC), immunologically castrated barrows (IC), and gilts... (Randomized Controlled Trial)
Randomized Controlled Trial
The study was performed to evaluate the effect of feeding ractopamine (RAC) to physically castrated barrows (PC), immunologically castrated barrows (IC), and gilts (gilts) using a randomized complete block design with a 3 × 3 factorial arrangement of treatments: 1) sex (PC, IC, and gilts) and 2) RAC inclusion level (0, 5, and 7.5 mg/kg). The IC received 2 doses of gonadotropin releasing factor analog-diphtheria toxoid conjugate (Improvest; Zoetis, Kalamazoo, MI) at the start of the study (wk 16 of age; 69.6 ± 2.96 kg BW) and 4 wk later. The study used 180 pigs housed in groups of 4 (5 groups/sex × RAC subclass) and was performed over a fixed time of 61 d with RAC being fed for the final 26 d of study. Diets were formulated to meet requirements of intact males for the first 35 d and of intact males fed 7.5 mg/kg RAC for the remainder of the study. Pigs had ad libitum access to feed and water throughout the study period. At the end of the study, pigs were harvested at a commercial facility and HCW and last rib backfat thickness were measured. There were no treatment interactions (P > 0.05) for any variables. For the overall study period, IC had greater (P ≤ 0.05) overall ADG compared to PC, which grew faster (P ≤ 0.05) than gilts (1,246, 1,083, and 1,025 g/d for IC, PC, and gilts, respectively; SEM = 20.3); ADFI was lower (P ≤ 0.05) for gilts than IC and PC, which had similar ADFI (3.36, 3.37, and 2.87 kg/d, respectively; SEM = 0.051); and G:F was greater (P ≤ 0.05) for IC than gilts and greater for gilts than PC (0.371, 0.322, and 0.358 kg/kg, respectively; SEM = 0.0039). For the period from the second dose to the end of study, IC had greater (P ≤ 0.05) ADG (28.6%), ADFI (12.3%), and G:F (14.3%) than PC. Carcass yield was lower (P ≤ 0.05) for IC compared to PC and gilts (72.8, 75.0, and 74.6%, respectively; SEM = 0.25). Feeding RAC increased (P ≤ 0.05) ADG (15.7 and 14.5% for 5 and 7.5 mg/kg, respectively), G:F (17.1 and 16.4%, respectively), carcass weight (3.7 and 3.2 kg, respectively), and carcass yield (1.0 and 1.0 percentage unit, respectively) compared to the control. These results highlight sex differences in and effects of RAC on growth and carcass characteristics and suggest that the relative response to RAC is similar in IC and PC.
Topics: Adrenergic beta-Agonists; Animal Feed; Animals; Body Composition; Diet; Female; Male; Orchiectomy; Phenethylamines; Swine; Vaccines, Contraceptive
PubMed: 25149340
DOI: 10.2527/jas.2014-7882 -
Journal of Animal Science Nov 2022The objective was to quantify the effects of age and ractopamine (RAC) on whole body oxygen consumption and Leu flux, and oxygen flux and metabolism of nitrogenous...
The objective was to quantify the effects of age and ractopamine (RAC) on whole body oxygen consumption and Leu flux, and oxygen flux and metabolism of nitrogenous compounds by the portal-drained viscera (PDV), liver, and hindquarters (HQ) of steers. Multicatheterized steers were fed a high energy diet every 2 h in 12 equal portions. Five younger steers (body weight, [BW] = 223 ± 10.1 kg) were 6 mo old and five older steers (BW = 464 ± 16.3 kg) were 14 mo old. Treatments were control (Cont) or 80 mg RAC per kg diet in a crossover design. Nitrogen (N) balance was measured on day 9 to 13. Whole body oxygen consumption and net flux were measured on day 11 and day 13, and net flux of N variables, Phe and Leu kinetics were measured on day 13. Whole body oxygen consumption increased (P < 0.05) in response to RAC in older but not younger steers. Retained N was greater (P = 0.009) for younger than older steers and increased (P = 0.010) with RAC in both ages of steers. Nitrogen retained as a percentage of N apparently absorbed increased (P < 0.05) in the older steers but not the younger steers in response to RAC. Oxygen uptake was greater (P < 0.05) in PDV, liver, and total splanchnic tissues in the younger steers and there was no response to RAC. In contrast, oxygen uptake in HQ increased (P < 0.05) with RAC in the older but not the younger steers. Concentration and net PDV release of α-amino N (AAN) were not affected by age or RAC. Uptake of AAN by liver decreased with RAC (P = 0.001). Splanchnic release of AAN was greater in younger steers (P = 0.020) and increased (P = 0.024) in response to RAC. For HQ tissues, uptake (P = 0.005) and extraction (P = 0.005) of AAN were lesser in older than younger steers and both increased (P = 0.001) in response to RAC. Based on Phe kinetics in HQ, RAC increased (P < 0.05) protein synthesis in older steers but not in younger steers. In contrast, protein breakdown decreased (P < 0.05) in response to RAC in younger steers. In response to RAC, protein degradation was less (P < 0.05) in younger than older steers. Based on Leu kinetics, whole body protein synthesis was greater in the younger steers (P = 0.022) but not altered in response to RAC. Ractopamine enhanced lean tissue growth by increasing supply of AAN to peripheral tissues and altering protein metabolism in HQ. These metabolic responses are consistent with established responses to RAC in production situations.
Topics: Cattle; Animals; Oxygen; Phenethylamines; Diet; Liver; Nitrogen; Body Weight
PubMed: 36094302
DOI: 10.1093/jas/skac304 -
Chemical Research in Toxicology May 2016The popularity of designer phenethylamines such as synthetic cathinones ("bath salts") has led to increased reports of life-threatening hyperthermia. The diversity of...
The popularity of designer phenethylamines such as synthetic cathinones ("bath salts") has led to increased reports of life-threatening hyperthermia. The diversity of chemical modifications has resulted in the toxicological profile of most synthetic cathinones being mostly uncharacterized. Here, we investigated the thermogenic effects of six recently identified designer phenethylamines (4-methylmethamphetamine, methylone, mephedrone, butylone, pentylone, and MDPV) and compared these effects to the established thermogenic agent 3,4-methylenedioxymethamphetamine (MDMA). Specifically, we determined the impact of a β-ketone, α-alkyl, or pyrrolidine functional group on core-body temperature changes. Sprague-Dawley rats (n = 5-6) were administered a dose (30 mg/kg, sc) of a designer phenethylamine or MDMA, and core body temperature measurements were recorded at 30 min intervals for 150 min post treatment. MDMA elicited the greatest maximum temperature change (ΔTmax), and this effect was significantly greater than that of its β-ketone analogue, methylone. Temperature-area under the curves (TAUCs) and ΔTmax were also significantly different between 4-methylmethamphetamine (4-MMA) and its β-ketone analogue mephedrone. Lengthening the α-alkyl chain of methylone to produce butylone and pentylone significantly attenuated the thermogenic response on both TAUCs and ΔTmax compared to those of methylone; however, butylone and pentylone were not different from each other. Pyrrolidine substitution on the N-terminus of pentylone produces 3,4-methylenedioxypyrovalerone (MDPV), which did not significantly alter core body temperature. Thermogenic comparisons of MDMA vs methylone and 4-MMA vs mephedrone indicate that oxidation at the benzylic position significantly attenuates the hyperthermic response. Furthermore, either extending the α-alkyl chain to ethyl and propyl (butylone and pentylone, respectively) or extending the α-alkyl chain and adding a pyrrolidine on the N-terminus (MDPV) significantly blunted the thermogenic effects of methylone. Overall, the present study provides the first structure-activity relationship in vivo toxicological analysis of designer phenethylamines.
Topics: Animals; Fever; Ketones; Male; Phenethylamines; Rats; Rats, Sprague-Dawley; Sympathomimetics
PubMed: 26954347
DOI: 10.1021/acs.chemrestox.6b00030 -
Analytical Chemistry Sep 2020Electrospray ionization mass spectrometry (ESI-MS) is widely used to analyze biomolecules, which are usually detected as protonated and cation-adducted molecules in the...
Electrospray ionization mass spectrometry (ESI-MS) is widely used to analyze biomolecules, which are usually detected as protonated and cation-adducted molecules in the positive-ion mode. However, phenethylamine derivatives, which are known as neurotransmitters and psychoactive drugs, undergo the protonation and subsequently lose NH during ESI. As a result, intense fragment-ion signals are observed in their ESI-MS spectra, which hamper the unambiguous identification of phenethylamine derivatives. To understand the mechanism of the loss of NH from these phenethylammoniums, the fragmentations of model 4-substituted phenethylamines were investigated and the fragment ions were identified as spiro[2.5]octadienyliums. Fragmentation was enhanced by the presence of electron-donating groups, and most substituted phenethylamines generated spiro[2.5]octadienyliums as fragment ions during ESI-MS, except those with strong electron-withdrawing groups. The quantitative analysis of phenethylamines by liquid chromatography tandem mass spectrometry is typically performed by multiple reaction monitoring using protonated molecules as the precursor. In contrast, the conversion of precursor ions from the protonated molecules into the spiro[2.5]octadienylium fragment improved the signal-to-noise ratio, allowing the quantitative analysis of phenethylamines with high sensitivity and accuracy.
Topics: Humans; Ions; Neurotransmitter Agents; Phenethylamines; Spectrometry, Mass, Electrospray Ionization
PubMed: 32786467
DOI: 10.1021/acs.analchem.0c02667