Phenylethylamine Derivatives Research Articles

A new derivatization reagent for determination of biogenic amines in wines

Fermented beverages are the main source of biogenic amines in our diet. Their levels are very difficult to minimize and important for the control of wine quality. Some of them are harmful to human health and methods of their analysis are still developed. In this paper, a new reagent, 1-fluoro-2-nitro-4-(trifluoromethyl)benzene, for precolumn derivatization of selected biogenic amines, and their chromatographic determination is described. The derivatives of histamine, tryptamine, tyramine and phenylethylamine were synthesized in high purity and characterized by 1H, 13C and 19F NMR. A convenient procedure based on the 1-fluoro-2-nitro-4-(trifluoromethyl)benzene has been developed for the determination of these amines in wine samples. The coefficient of variation, <2.5% for all samples, the recovery ≈100%, demonstrate repeatability and accuracy of procedure. It is convenient, shows lower solvent consumption, and takes less time in comparison to previously described methods.

ChemInform Abstract: Palladium‐Catalyzed Oxalyl Amide Directed Silylation and Germanylation of Amine Derivatives.

AbstractConditions for the ortho‐selective trimethylsilylation of oxalyl amide protected benzylamine and phenylethylamine derivatives are developed which tolerate a diverse range of functional groups.

Pd(ii)-catalyzed remote regiodivergent ortho- and meta-C-H functionalizations of phenylethylamines.

Site selectivity control is of vital importance in the direct functionalization of inert C-H bonds. Reported here is a novel example of remote regiodivergent ortho- and meta-C-H bond functionalizations of phenylethylamine derivatives by using a novel 2-cyanobenzoyl group as the original directing functionality, where the regioselectivity was adjusted by a methylation. The potential of the method was exemplified by sequential functionalizations of both ortho- and meta-C-H bonds of a phenylethylamine derivative in a streamlined manner.

A family of homochiral spin-crossover iron(II) imidazole Schiff-base complexes

Four novel homochiral mononuclear spin-crossover iron(II) complexes 1–4 have been successfully synthesized by subcomponent self-assembly of Fe(ClO4)2, 1-substituted imidazole-2-carboxaldehyde and optical phenylethylamine derivatives. X-ray crystallography revealed that the iron(II) center in 1–4 assumed an octahedral coordination environment with 6 N donor atoms from three unsymmetrical bidentate chiral Schiff-base ligands. [Fe(Ln)3]2+ components were chiral with either Λ or Δ configuration due to the screw coordination arrangement of the chiral ligands around Fe(II) center. Circular dichromism spectra confirmed the presence of non-racemic chiral metal centers in solution for 1–4. Magnetic measurements revealed that 1–4 displayed obviously spin-crossover behavior at 257, 375, 137 and 282K, respectively. The different SCO behaviors of 1–4 may result from substitution effect, packing mode, and intermolecular interactions.

Glial Cell Response to 3,4-(±)-Methylenedioxymethamphetamine and Its Metabolites

3,4-(±)-Methylenedioxymethamphetamine (MDMA) and 3,4-(±)-methylenedioxyamphetamine (MDA), a primary metabolite of MDMA, are phenylethylamine derivatives that cause serotonergic neurotoxicity. Although several phenylethylamine derivatives activate microglia, little is known about the effects of MDMA on glial cells, and evidence of MDMA-induced microglial activation remains ambiguous. We initially determined microglial occupancy status of the parietal cortex in rats at various time points following a single neurotoxic dose of MDMA (20mg/kg, SC). A biphasic microglial response to MDMA was observed, with peak microglial occupancy occurring 12- and 72-h post-MDMA administration. Because direct injection of MDMA into the brain does not produce neurotoxicity, the glial response to MDMA metabolites was subsequently examined in vivo and in vitro. Rats were treated with MDA (20mg/kg, SC) followed by ex vivo biopsy culture to determine the activation of quiescent microglia. A reactive microglial response was observed 72 h after MDA administration that subsided by 7 days. In contrast, intracerebroventricular (ICV) administration of MDA failed to produce a microglial response. However, thioether metabolites of MDA derived from α-methyldopamine (α-MeDA) elicited a robust microglial response following icv injection. We subsequently determined the direct effects of various MDMA metabolites on primary cultures of E18 hippocampal mixed glial and neuronal cells. 5-(Glutathion-S-yl)-α-MeDA, 2,5-bis-(glutathion-S-yl)-α-MeDA, and 5-(N-acetylcystein-S-yl)-α-MeDA all stimulated the proliferation of glial fibrillary acidic protein-positive astrocytes at a dose of 10 µM. The findings indicate that glial cells are activated in response to MDMA/MDA and support a role for thioether metabolites of α-MeDA in the neurotoxicity.

Indole alkaloids from the marine bacterium Pantoea agglomerans

Five indole alkaloids and two phenylethylamine derivatives were isolated from the ethyl acetate extract of the fermentation broth of the marine bacterium Pantoea agglomerans P20-14. Their structures were identified as N-(4-hydroxyphenethyl)-2-(1H-indol-3-yl)acetamide (1), 3-(p-hydroxy)benzoyl indole (2), 1,2-di(1H-indol-3-yl)ethane (3), 1H-indole-3-carboxylic acid (4), 2-hydroxy-1-(1H-indol-3-y1)ethanone (5), N-acetyltyramine (6), and 2-(4-hydroxyphenethyl)-N-phenylacetamide (7). Compound 1 is a new indole alkaloid and compounds 2 and 3 are new natural products.The structures of the seven compounds were established on the basis of chemical and spectroscopic methods. The spectroscopic data of compound 2 is provided for the first time.

Study of the photocatalytic transformation of synephrine: a biogenic amine relevant in anti-doping analysis

The occurrence of some cases of positive results in anti-doping analysis of octopamine requires clarification as to whether its methylated derivative synephrine could be a metabolic precursor of octopamine itself. Synephrine is a natural phenylethylamine derivative present in some food supplements containing Citrus aurantium, permitted in sport regulations. A simulative laboratory study had been done using a photocatalytic process, to identify all possible main and secondary transformation products, in a clean matrix; these were then sought in biological samples obtained from three human volunteers and four rats treated with synephrine; the parent compound and its new potential metabolic products were investigated in human urine and rat plasma samples. The transformation of synephrine and octopamine and the formation of intermediate products were evaluated, adopting titanium dioxide as photocatalyst. Several products were formed and characterized using the HPLC-HRMS(n) technique. The main intermediates identified in these experimental conditions were compared with the major synephrine metabolites found in in vivo studies on rats and humans. Some more oxidized species, already formed in the photocatalytic process, were also found in urine and plasma samples of treated animals. These new findings could be of interest in further metabolism studies. The main photocatalytic pathway involving synephrine appears to be N-demethylation to give octopamine. On the contrary, we demonstrate the inconsistency of this reaction in both rat and human in vivo determinations, resulting in forensic importance.

Analytical methods for venlaflaxine hydrochloride and metabolites determinations in different matrices

There may be significant variation in stereoisomers related to distribution, bioavailability, metabolism, and excretion. Venlafaxine is a bicyclic phenylethylamine derivative, a unique antidepressant,which structurally differs from other currently available anti-depressants. Its mechanism of action is believed to be associated with triggering neurotransmitter activity in the CNS. This drug is a racemic mixture of the (−)-R-enantiomer and (+)-S-enantiomer. O-desmethylvenlaflaxine is the major metabolite formed after first pass metabolism with similar potency as parent drug. Two less potent minor metabolites are N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. Thus, summarization of all of the analytical methods for the determination of venlaflaxine alone, in combination, or in the presence of other metabolites, is summarized. The keywords used for search were “Analytical methods on Venlaflaxine,” “Determination of venlaflaxine,” “Determination of venlaflaxine and metabolites,” and “Venlaflaxine plasma determinations.” Eight spectrophotometry, 26 chromatography, and seven electroanalytical methods were found for the determination of venlaflaxine alone, in formulations, biological matrices, and simultaneous determinations with metabolites and other anti-depressants. Short review of pharmacological activity of venlaflaxine and its metabolites are also presented.

Synthesis and Separation of the Enantiomers of the Neuropeptide S Receptor Antagonist (9R/S)-3-Oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic Acid 4-Fluoro-benzylamide (SHA 68)

This study reports the synthesis, chromatographic separation, and pharmacological evaluation of the two enantiomers of the neuropeptide S receptor (NPSR) antagonist (9R/S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68). The (9R)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (compound 10) and (9S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (compound 10a) were synthesized and their purity assessed by chiral chromatography. The absolute configuration of the enantiomer 10 has been assigned from the crystal structure of the corresponding (S)-phenyl ethyl amine derivative 8. Calcium mobilization studies performed on cells expressing the recombinant NPSR demonstrated that compound 10 is the active enantiomer while the contribution of 10a to the NPSR antagonist properties of the racemic mixture is negligible.

ChemInform Abstract: Improved Synthesis of Phenylethylamine Derivatives by Negishi Cross‐Coupling Reactions.

AbstractN‐Trifluoroacetyl‐protected (β‐aminoalkyl)arenes are synthesized by conversion of the corresponding (aminoalkyl) iodides into organozinc iodides followed by the coupling reaction with aryl iodides.

Optically Active Films Fabricated from Poly(Allylamine Hydrochloride) and R-(+)-1-Phenylethylamine Derivatives of Poly(Ethylene-Alt-Maleic Acid) with Different Degrees of Substitution

Optically active films were built up from poly(allylamine hydrochloride) (PAH) and R-(+)--phenylethylamine derivatives of poly(ethylene-alt-maleic acid) (PEMA-PEA) with substituting degrees (DS) ranging from 0.48 to 0.97. The growth of the film was monitored with the circular dichroism (CD) and the UV spectrophotometer and the effect of DS of PEMA-PEA on the film was investigated. UV and CD data show the growth regime of the multilayer changing from exponential to linear. Deposition amounts of PEMA-PEA in multilayer films decrease with the increase in DS of PEMA-PEA, which was explained based on the conformation of the polyelectrolyte and the charge overcompensation as the polyelectrolyte was deposited on the surface of the film. These results are of benefit to the development of multilayer films for the chiral separation of enantiomers.

Improved synthesis of phenylethylamine derivatives by Negishi cross-coupling reactions

Trifluoroacetamido-protected β-aminoalkylzinc iodides undergo Negishi cross-coupling reaction with aryl iodides in moderate to excellent yields (42–84%) based on the corresponding trifluoroacetamido-protected β-aminoalkyl iodides, employing a catalyst prepared in situ from Pd 2(dba) 3 and SPhos (1:2 M ratio). In general, meta- and para-substituted aryl iodides give good results using relatively low levels of catalyst [0.25 mol % Pd 2(dba) 3], but more hindered ortho-substituted examples require higher catalyst loadings. The preparation of trifluoroacetamido-protected β-aminoalkyl iodides is straightforward, and the intermediates are significantly more stable than the corresponding Boc-protected derivatives.

Impurity Profile Study of Venlafaxine Hydrochloride, an Antipsychotic Drug Substance

Venlafaxine hydrochloride is a phenyl ethylamine derivative, used for the treatment of depression. During the process development of venlafaxine hydrochloride, six process-related potential impurities were detected in high-performance liquid chromatography. All these impurities were identified, synthesized, and subsequently characterized by their respective spectral data (IR, mass, 1H NMR, and 13C NMR) as described in this article.

Chiral amine-induced stereoselectivity in trans-β-lactam formation via Staudinger cycloaddition

A series of chiral trans-β-lactams was obtained via Staudinger cycloaddition with low to moderate diastereoselectivity (up to 54% de) induced by a chiral amine component of the imine. It was shown that the direct connection of nitrogen to a chiral centre is crucial to induce chirality; moderate asymmetric induction was achieved by using isomeric 1-phenylethylamines, which are among the cheapest chiral sources on the market, while low diastereoselectivity was obtained from 3-aminomethylpinane, where the chiral centres are distant from nitrogen by a methylene group. It was shown, that an increase of the reaction temperature from 110 °C to 140 °C led to commensurable results but speeded-up the transformation significantly. The absolute configurations of phenylethylamine derivatives were determined by X-ray analysis of selected samples.

GPR12 Selections of the metabolites from an endophytic Streptomyces sp. Asociated with Cistanches deserticola

An endophytic Streptomyces sp. (AC-2) was isolated from the root of Cistanches deserticola Y.C.Ma.. Chemical investigations of the culture broth of AC-2 afforded fifteen compounds including K1115 A (1), tyrosol (2), phenylethylamine derivatives (3, 4), cyclic dipeptides (5-8), nucleosides and their aglycones (9-13), N-acetyltryptamine (14), and pyrrole-2-carboxylic acid (15). Only tyrosol can promote an increase of intracellular cAMP special on GPR12 transfected cells, such as CHO and HEK293, which means it may be a possible ligand for GPR12.

Recent Paramethoxymethamphetamine (PMMA) Deaths in Taiwan

Paramethoxyamphetamine (PMA) and paramethoxymethamphetamine (PMMA) are methoxylated phenylethylamine derivatives that have been banned in Taiwan since December 2005. The case history and pathological and toxicological findings of eight recent PMMA fatalities were investigated. All specimens from these cases were initially identified by an AxSYM fluorescence polarization immunoassay screening test for amphetamines with a 300 ng/mL cutoff. Specimens screened positive were confirmed and quantitated by gas chromatography-mass spectrometry. The mean age of these PMMA-related fatalities was 18.9 +/- 4.4 years in the range of 14-25. Seven (87.5%) of these eight cases were men. The mean, standard deviation, and range of PMA found in the heart blood collected from these 8 cases were 0.213, 0.144, and 0.079-0.489 microg/mL, respectively. The corresponding data for PMMA were 4.312, 4.806, and 1.208-15.824 microg/mL, respectively. Other drugs, such as MDA, MDMA, ketamine, norketamine, hydroxymidazolam, methamphetamine, and pentobarbital, were also found in these cases.

Resolution of methyl-1-phenylethylamines by acidic derivatives of 1-phenylethylamine

Methyl-1-phenylethylamines were resolved by phenylethylamine derivatives formed with a homologous series of dicarboxylic acids. The structure of the 4-methyl-1-phenylethylamine N-(1-phenylethylamine) succinic acid monoamide diastereoisomeric salt was investigated by single crystal X-ray diffraction.

More potent inhibition of human CYP2A6 than mouse CYP2A5 enzyme activities by derivatives of phenylethylamine and benzaldehyde

1. A rapid 96-well plate assay method was developed and validated to measure liver microsomal coumarin 7-hydroxylation in vitro. 2. The method was used to test inhibition of human and mouse CYP2A enzymes by three phenylethylamine derivatives 2- (p -tolyl)-ethylamine, amphetamine, 2-phenylethylamine and benzaldehyde, and two of its derivatives, 4-methylbenzaldehyde and 4-methoxybenzaldehyde. 3. The benzaldehyde derivatives were more potent inhibitors of CYP2A5 than the phenylethylamines. The K ic value of 4-methylbenzaldehyde was 3.4 µ M and for 4-methoxybenzaldehyde it was 0.86 µ M for CYP2A5. 4. Amphetamine is a weak inhibitor of CYP2A6, whereas benzaldehyde is a suicide inhibitor with K inact = 0.16 min − 1 and K I = 18 µ M. The K ic values of 2-phenylethylamine, 2- (p -tolyl)-ethylamine, 4-methylbenzaldehyde and 4-methoxybenzaldehyde were 1.13, 0.23, 0.36 and 0.73 µ M for CYP2A6, respectively. 5. Novel potent inhibitors were found for CYP2A6 and, except for 4-methoxybenzaldehyde, all the compounds inhibited CYP2A5 and CYP2A6 enzymes differentially. These data add to the refinement of CYP2A enzyme active sites and provide chemical leads for developing novel chemical inhibitors of the CYP2A6 enzyme.

Three cases of fatal paramethoxyamphetamine overdose.

Two recent cases of death due to paramethoxyamphetamine (PMA), a methoxylated phenylethylamine derivative, are described and compared with a previous PMA death that occurred in this province in 1985. The deceased were 18 or 19 years of age and were reported to have ingested either methylenedioxymethamphetamine (MDMA, Ecstasy) or methylenedioxyamphetamine (MDA) prior to their deaths. Concentrations of PMA were measured in both peripheral and heart blood samples using gas chromatography equipped with a nitrogen-phosphorus detector. PMA results in the most recent cases were 0.6 mg/L and 1.3 mg/L in the peripheral blood samples, and corresponding heart blood samples were 0.7 mg/L and 2.3 mg/L, respectively. In the 1985 case, the femoral blood concentration was 0.6 mg/L, and the heart blood concentration was 0.8 mg/L. Significant differences between heart and peripheral blood concentrations were observed in two of the three cases, which may indicate the potential for postmortem redistribution of PMA.

Structure–activity studies leading to (−)1-(Benzofuran-2-yl)-2-propylaminopentane, ((−)BPAP), a highly potent, selective enhancer of the impulse propagation mediated release of Catecholamines and Serotonin in the brain

The catecholaminergic and serotoninergic neurons in the brain change their performance according to the physiological need via a catecholaminergic/serotoninergic activity enhancer (CAE/SAE) mechanism. Phenylethylamine (PEA), tyramine and tryptamine are the presently known endogenous CAE/SAE substances which enhance the impulse propagation mediated release of catecholamines and serotonin in the brain. A PEA derivative, (−)deprenyl (selegiline), known as a selective inhibitor of MAO-B, is for the time being the only CAE/SAE substance in clinical use. Aiming to develop a selective CAE/SAE substance much more potent than (−)deprenyl, a series of new 1-aryl-2-alkylaminoalkanes, structurally unrelated to PEA and the amphetamines, was designed and prepared. Among them, (−)1-(benzofuran-2-yl)-2-propylaminopentane ((−)BPAP) was selected as a promising candidate substance for further studies. (−)BPAP significantly enhanced in rats the impulse propagation mediated release of catecholamines and serotonin in the brain 30 min after acute injection of 0.36 nmol/kg sc. In the shuttle box, (−)BPAP was in rats about 130 times more potent than (−)deprenyl in antagonizing tetrabenazine induced inhibition of performance. (±)BPAP protected cultured hippocampal neurons from the neurotoxic effect of β-amyloid in 10 −14−10 −15 M concentration.