Amine Pathways Research Articles

A DFT study of the mechanism of palladium-catalyzed alkoxycarbonylation and aminocarbonylation of alkynes: Hydride versus amine pathways

A DFT study on the palladium-bisphosphine catalyzed alkoxycarbonylation and aminocarbonylation of alkyne (propyne) is reported. The theoretical study explores the feasibility and the regioselectivity control of two independent mechanisms: the first is based on the active intermediate [Pd(II)(P 2)(H)] + (where P 2 = PH 2CH 2CH 2CH 2CH 2PH 2) for the alkoxycarbonylation reaction, and the second is based on the active species [Pd(II)(P 2)(NR 2)] + for the aminocarbonylation reaction. The study explains the role of solvent in increasing the yield and in controlling the selectivity of reaction to produce selectively the trans isomer in the alkoxycarbonylation reaction (hydride cycle) and the gem isomer in the aminocarbonylation reaction (amine cycle). In hydride cycle, the regioselectivity is mainly determined by the stability of the complex [Pd(II)(P 2)(COC 3H 5)(CH 3CN)] +; however, for the amine cycle, the regioselectivity is determined by the stability of the complex [Pd(II)(P 2)(C 3H 5CON(CH 3) 2)] +. The calculations reveal that ligand simplification is not valid in addressing the regioselectivity behavior of alkoxycarbonylation and aminocarbonylation reactions. The kinetic data for the formation of the two key complexes show no difference between the gem and trans isomers which predict the regioselectivity to be a thermodynamically controlled process.

Genetic variation in the bioactivation pathway for polycyclic hydrocarbons and heterocyclic amines in relation to risk of colorectal neoplasia

Animal work implicates chemical carcinogens, such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic aromatic amines (HAAs) as contributing to the development of colorectal cancer (CRC). The epidemiologic evidence, however, remains inconsistent possibly due to intra-individual variation in bioactivation of these compounds. We conducted a case-control study of colorectal adenoma (914 cases, 1185 controls) and CRC (496 cases, 607 controls) among Japanese Americans, European Americans and Native Hawaiians to investigate the association of genetic variation in the PAH and HAA bioactivation pathway (CYP1A1, CYP1A2, CYP1B1, AHR and ARNT) identified through sequencing with risk of colorectal neoplasia, as well as their interactions with smoking and intakes of red meat and HAAs. The A allele for ARNT rs12410394 was significantly inversely associated with CRC [odds ratios (ORs) and 95% confidence intervals (CIs) for GG, AG and AA genotypes: 1.00, 0.66 (0.48-0.89), 0.54 (0.37-0.78), P(trend) = 0.0008] after multiple comparison adjustment. CYP1A2 rs11072508 was marginally significantly associated with CRC, where each copy of the T allele was associated with reduced risk (OR: 0.72, 95% CI: 0.58-0.88, P(trend) = 0.0017). No heterogeneity of genetic effects across racial/ethnic groups was detected. In addition, no significant interaction was observed after adjusting for multiple testing between genetic variants and pack-years of smoking, intake of red meat or HAAs (PhIP, MeIQx, Di-MeIQx or total HAAs) or NAT2 genotype (Rapid versus Slow or Intermediate). This study suggests that the genomic region around ARNT rs12410394 may harbor variants associated with CRC.

An Experimental−Theoretical Study of the Factors That Affect the Switch between Ruthenium-Catalyzed Dehydrogenative Amide Formation versus Amine Alkylation

A ruthenium(II) diamine complex can catalyze the intramolecular cyclization of amino alcohols H2N(CH2)nOH via two pathways: (i) one yields the cyclic secondary amine by a redox-neutral hydrogen-borrowing route with loss of water; and (ii) the second gives the corresponding cyclic amide by a net oxidation involving loss of H2. The reaction is most efficient in cases where the product has a six-membered ring. The amide and amine pathways are closely related: DFT calculations show that both amine and amide formations start with the oxidation of the amino alcohol, 5-amino-1-pentanol, to the corresponding amino aldehyde, accompanied by reduction of the catalyst. The intramolecular condensation of the amino aldehyde takes place either in the coordination sphere of the metal (path I) or after dissociation from the metal (path II). Path I yields the Ru-bound zwitterionic form of the hemiaminal protonated at nitrogen, which eliminates H2, forming the amide product. In path II, the free hemiaminal dehydrates, givin...

Anxiety‐Related Behavior and Biogenic Amine Pathways in the Rat following Bilateral Vestibular Lesions

Many clinical studies have reported that patients with vestibular disorders have a high rate of anxiety disorders and depression. By contrast, there have been few studies of affective behavior in animals following vestibular lesions. Recent studies using the vestibular impaired ci2/ci2 mutant rat strain have shown that rather than preferring the closed arm of the elevated plus maze, as rats would normally, they make more open-arm entries and spend more time on the open arms compared to wild-type controls. In the open-field maze, rather than preferring to explore the outer zone near the walls ("thigmotaxis"), ci2/ci2 rats prefer the inner region of the maze. In rats with bilateral vestibular deafferentation (BVD), similar results were obtained. Compared to sham controls, at 3 and 5 months post-op, BVD rats spent more time on the open arms of the elevated plus maze, more time in the inner zone of the open-field maze, and failed to learn inhibitory avoidance in the elevated T maze. They did not display increased hyponeophagia; however, they did exhibit a decrease in social interaction. Blood corticosterone levels were not significantly different from sham controls. At 6 months post-op, BVD rats demonstrated circumscribed changes in the expression of tyrosine hydroxylase, the serotonin transporter, and tryptophan hydroxylase, in various regions of the medial temporal and frontal lobes, suggesting changes in biogenic amine pathways.

UGT1A1 and UGT1A9 functional variants, meat intake, and colon cancer, among Caucasians and African-Americans

Glucuronidation by the UDP-glucuronosyltransferase enzymes (UGTs) is one of the primary detoxification pathways of dietary heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). In a population-based case–control study of 537 cases and 866 controls, we investigated whether colon cancer was associated with genetic variations in UGT1A1 and UGT1A9 genes and we determined if those variations modify the association between colon cancer and dietary HCA and PAH exposure. We measured functional UGT1A1 polymorphisms at positions -53 (*28; A(TA)6TAA to A(TA)7TAA), -3156 (G > A), -3279 (T > G) and the UGT1A9-275(T > A) polymorphism, and found no association with colon cancer overall. However, when stratified by race, the UGT1A1-3279 GG/TG intermediate/low activity genotypes were associated with an increased risk of colon cancer (odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.1–2.0) in Caucasians. This finding is also supported by haplotype analyses where the UGT1A1-3279G-allele-bearing haplotype is overrepresented in case group. Overall, UGT1A1-53 and -3156 genotypes modified the association between dietary benzo( a)pyrene (BaP) and colon cancer ( P for interaction = 0.02 and 0.03, respectively). The strongest association was observed for those with <7.7 ng/day BaP exposure and the low activity genotypes, for both UGT1A1*28/*28 (OR = 1.8, 95% CI = 1.1–2.9) and -3156AA (OR = 1.7, 95% CI = 1.0–3.0), compared to ≥7.7 ng/day and combined high/intermediate genotypes. These data support a hypothesis that UGTs modify the association between meat-derived PAH exposure and colon cancer by their role in the elimination of dietary carcinogens.

Monoamine transporter and enzyme expression in the medial temporal lobe and frontal cortex following chronic bilateral vestibular loss

Peripheral vestibular damage has been reported to be associated with a high incidence of anxiety disorders and depression. In this study we investigated whether chronic bilateral vestibular deafferentation (BVD) would affect the expression of several biogenic amine enzymes and transporters in the medial temporal lobe (CA1, CA2/3, dentate gyrus (DG), entorhinal (EC) and perirhinal cortices (PRC)) and frontal lobes (FL) of rats. BVD was not associated with any significant differences in dopamine beta-hydroxylase or the dopamine transporter in any brain region studied. There was a significant decrease in tyrosine hydroxylase expression only in the FL and a significant decrease in the expression of the serotonin transporter in the FL and CA1 in BVD rats. Tryptophan hydroxylase showed a significant increase in expression in the FL, CA2/3, and DG and a significant decrease in the EC. These results suggest that biogenic amine pathways in the medial temporal lobe and FL undergo changes following BVD.

Gas-Phase Reactions of Lithium Dimethylaminoborohydride and Related Species

[reaction: see text] Ab initio and density functional theory (DFT) calculations were used to examine the mechanisms of reduction and amination of chloromethane by lithium dimethylaminoborohydride (LAB) in the gas phase. For comparison, the amination of chloromethane by lithium dimethylamide and the reduction by borane, diborane, and borohydride ions were also examined. The reduction of chloromethane by LAB occurred most readily from a conformation that allowed coordination of the lithium atom to the chloride leaving group, and the most favorable amination pathway occurred by a backside attack of the nitrogen nucleophile on chloromethane.

Mass spectral fragmentation pathways of propranolol related beta-fluorinated amines studied by electrospray and electron impact ionization.

Propranolol, its 1"-mono-, di-, and trifluorinated analogs, and other related compounds were analyzed under electrospray ionization ion trap collision-induced dissociation (ESI-CID) and electron impact (EI) conditions. Interesting trends were observed in the fragment ions formed in both cases. Under ESI conditions, the abundances of product ions easily explained by protonation on the amine nitrogen decreased relative to the abundances of those formed from the ether-protonated species as the number of fluorines increased from zero to three. Under EI conditions, the distribution of fragment ions was shifted away from those arising from a nitrogen-centered cation radical and toward those arising from an ether oxygen-centered cation radical. The changes observed in apparent molecular sites of protonation and of ion radical formation in the mass spectra are consistent with the electron-withdrawing effects of the sequentially added fluorines. These effects are correlated with changes in solution phase pK( a)'s of the fluorinated amines.

Levels of Biogenic Amines in the Brain during Pupal and Adult Development of the Silkworm, Bombyx mori

Abstract Levels of a wide range of biogenic amines and related metabolites were determined in the brain of the silk­ worm, Bomby mori, during pupal and adult development using a three-dimensional HPLC system with multiple coulometric electrochemical detection. In the brain of the female adults, metabolic pathways such as tyrosine (TYR-4)-&gt;dihydroxyphenylalanine (L -DOPA)-dopamine (DA), TYR-4-&gt;tyramine (TYRA), and tryptophan (TRP)-&gt;5-hydroxytryptamine (5-HT) were identified. At this stage, 3,4-dihydroxyphenyleth-ylene (DOPAC) was also detected. Metabolic pathways of biogenic amines in the brain from pupal to adult stages are discussed.

Catabolism of dopamine and 5-hydroxytryptamine by monoamine oxidase in the ixodid tick, amblyomma hebraeum

The purpose of this study was to assess biogenic amine catabolism in Amblyomma hebraeum Koch (an African cattle tick). We assayed haemolymph and saliva for a variety of biogenic amines (usually following injection of substrate into the haemolymph) in partially fed females using HPLC coupled to electrochemical detection. Dopamine (DA) and 5-hydroxytryptamine (5-HT) were rapidly converted to dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole-acetic acid (5-HIAA) respectively, indicating that monoamine oxidase (MAO) constitutes a major catabolic pathway for biogenic amines in this species. We could not detect N-acetylated or γ-glutamyl conjugated metabolites of these important neurotransmitters. [In a few samples we looked for but could not detect homovanillic acid or 3-methoxytyramine ( O-methylated metabolites of DOPAC and DA respectively).] Deprenyl was about 44–72 times more potent an inhibitor of MAO than clorgyline when either DA or 5-HT was offered as substrate, suggesting that this MAO is of the MAO B type. Conversion of DA to DOPAC was also detected in several tissues incubated with DA in vitro; in descending order of MAO activity (pmol mg −1h −1 at about 18°C) tissues tested were: skeletal muscle (∼100), Malpighian tubule (∼50), ovary (∼45), salivary gland (∼30), midgut (∼20), and haemolymph (∼4–5). This study suggests that ticks differ considerably from insects in utilizing MAO as an important metabolic pathway for biogenic amines.

N-Acetyltransferases, O-Acetyltransferases, and N, O-Acetyltransferases: Enzymology and Bioactivation

Publisher Summary Acetyltransferases play a central role in the metabolic disposition, detoxication, and bioactivation of a diverse group of drugs—carcinogens and other xenobiotics. Acetylation is a major metabolic pathway for primary aromatic amines (arylamines, ArNH) and hydrazines. In earlier times, acetylation was the principal mechanism for termination of the tuberculostatic action of isoniazid. The importance of human acetylation capacity is further illustrated by the propensity of phenotypically slow acetylator patients to experience methemoglobinemia or drug-induced lupus erythematosus or both when treated either with arylamine drugs or with various agents that contain the hydrazine moiety. The mutagenicity and carcinogenicity of arylamines along with thedocumented environmental and dietary exposure to these agents have stimulated numerous investigations of arylamine metabolism. Thus, the premise that formation of unreactive arylamides by N-acetylation of arylamines is primarily a detoxification process and that oxidative Nhydroxylation is a toxification reaction is supported by a substantial body of evidence. However, the demonstration that arylamine N- acetyltransferases are versatile enzymes that can catalyze the conversion of both N-arylhydroxylamines and N-arylhydroxamic acids to reactive, electrophilic metabolites has broadened the scope of research on acetyltransferases, which are now included among those conjugation systems that play important roles in the bioactivation of xenobiotics.

Etoposide(VP16): Chemical reactivity of etoposide ortho-quinone with amines and thiols

Reaction of etoposide ortho-quinone with primary amines results in products derived from transmination and reductive amination pathways. In contrast, thiols afford Michael adducts and/or thiol-quinone redox products.

Further studies on the comutagenic activity of cigarette smoke condensate

The comutagenic effect exerted by cigarette smoke condensate (CSC) was investigated. In vitro experiments with Salmonella typhimurium strains TA98 and TA98/1,8DNP 6 indicated that CSC specifically enhances the mutagenicity of polyaromatic amines such as 2-aminofluorene, 2-acetylaminofluorene, 4-acetylaminofluorene and 2-aminoanthracene. The pattern of comutagenicity of CSC was shown to differ from that of norharman, a tobacco-related known comutagenic substance. Both black and blond tobacco CSCs proved to interact synergistically with 2-aminoanthracene mutagenicity. Chemical fractionation of CSC indicates the occurrence of comutagenic substance(s) in both neutral and basic components. Further in vitro experiments with 2-acetylaminofluorene metabolites and derivatives suggest that the comutagenic effect of CSC could involve later step(s) in the metabolic activation of fluorenylamines, i.e., the conversion of hydroxylamines into ultimate reactive species. The possible occurrence of a synergistic interaction of CSC with chemical mutagens in vivo was evaluated. Administration of 2-aminoanthracene/CSC mixtures, previously shown to be comutagenic in vitro, failed to demonstrate a synergistic effect in SCE induction in bone marrow cells of mice. This apparent discrepancy may rely on divergences in the activation pathways of polycyclic amines in vitro and in vivo.

Biogenic amine levels in the central nervous system and haemolymph of the silkworm, Bombyx mori

1. A wide range of biogenic amines and related metabolites were quantified in the silkworm, Bombyx mon from fourth instar to post-spinning stage using a three-dimensional HPLC system with multiple coulometric electrochemical detection. 2. In the central nervous system, metabolic pathways such as tyrosin (TYR-4)-dopa ( L-DOPA)-dopamine (DA), TYR-4-tyramine (TYRA), tryptophan (TRP)-5-hydroxytryptamine (5-HT) were found. In some stages, normetanephrine (NMN), 3,4-dihydroxyphenylethylene (DOPAC) and 5-hydroxyindoleacetic acid (5HIAA) were detected. 3. In the haemolymph, TRY-4-L-DOPA-DA pathway was mainly found. 3-Methoxy-4-hydroxy- phenyl glycol (MHPG) in fourth instar and norepinephrine (NE) in fifth instar were also detected. 5-HT was lacking. 4. Metabolic pathways of biogenic amines in the central nervous system and haemolymph were discussed.

Integrated genetic databases in the study of neuropsychiatric diseases: Inborn errors of cerebral metabolic pathways?

1. 1. Genetic databases.are an expanding and readily accessible repository of information on the mapping and sequencing of the human genome, and that of other model organisms. The integration and application of this information to neuropsychiatric disease is illustrated using neuroendocrine and neuropharmacologic data, computerized and other genetic databases. 2. 2. This computer-assisted integrated approach to knowledge structures permits the rapid generation of hypotheses, the prompt identification of candidate gene loci, an explanation for genetic heterogeneity, and strategies for the use of potential linked markers. 3. 3. Results using this integrated search strategy demonstrate that over 30 candidate loci for neuropsychiatric disease have currently been mapped in man (spread over 14 chromosomes in the human genome), and that at least 6 homologous loci have been mapped in mouse. 4. 4. Using a metabolic pathway approach, it can be shown that the best current candidate gene locus for a subtype of schizophrenia located on chromosome 5q11–13 (HGML10 # SCZD1 and OMIM #181510) is in the serotonergic pathway i.e. a receptor for 5-hydroxytryptamine (subtype 1A; HGML10 #HTR1A) which also maps in the same chromosomal region. 5. 5. Parallels are suggested between inborn errors of metabolic pathways in the somatic endocrine system (using insulin-dependent diabetes mellitus as a paradigm) and the neurotransmitter and hormonal systems within the brain. 6. A subset of neuropsychiatric disorders may thus be viewed as inborn errors of cerebral metabolic pathways primarily affecting the biogenic amine pathways.

Alteration of biogenic amines in mouse brain regions by alkylating agents. I. Effects of aflatoxin B1 on brain monoamines concentrations and activities of metabolizing enzymes

Young adult male CD-1 mice were treated orally twice weekly for three weeks with 0, 0.05, 0.15 or 0.65 mg/kg of aflatoxin B1 (AFB1) in corn oil. Two days after the last dose, the mice were killed by decapitation and the concentrations of the brain catecholamines, norepinephrine (NE), and dopamine (DA), and their metabolites, 3-methoxy-4-hydroxymandelic (VMA), homovanillic acid (HVA) and dihydroxyphenyl acetic acid (DOPAC) and the indoleamine serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) were determined by high pressure liquid chromatography in six discrete brain regions. Major effects of AFB1 were found in the concentrations of NE in most brain areas. Endogenous concentrations of DA were increased in the striatum and hypothalamus. The VMA level in the hypothalamus and striatum were decreased by the treatment. The activity of tyrosine hydroxylase, tryptophan hydroxylase, amino acid decarboxylase and monoamine oxidase (the enzymes important in synthetic and degradation pathways of biogenic amines) were investigated. Alterations in biogenic amine concentrations were often consistent with the changes observed in metabolizing enzymes. There was an increase noted in tryptophan hydroxylase activity. Activities of amino acid decarboxylase and monoamine oxidase were increased although the changes were not consistent in all regions or at all dose levels of AFB1. These results suggest that dietary exposure to AFB1 diets may cause alterations in various biogenic amine concentrations and related metabolizing enzymes.

Tourette's medications: Effect on minor oxidative and reductive pathways of biogenic amines

The effect of acute treatment of two major Tourette's drugs, haloperidol and pimozide given 60 mg/kg, IP over 48 hr, on hepatic alcohol dehydrogenase (L-ADH) and aldehyde dehydrogenase was studied in the female mouse. The effect of these drugs on heart cytoplasmic lactate dehydrogenase (H-LDH) isoenzyme LDH1 (M) and LDH2 (H) was also measured. Both haloperidol and pimozide significantly inhibited cytoplasmic L-ADH and L-ALDH from controls. Conversely, the haloperidol treatment was associated with induction of both H-LDH isoenzymes studied. Injection of pimozide, 25 mg/kg, IP, to rats with preference to ethanol drinking, caused aversion to voluntary intake of 5% ethanol consumption. This suggests that pimozide produced inhibition of L-ADH in another species and thereby causing aversion to ethanol drinking or may be related to dopaminergic antagonist property. This inhibition of these drugs on the oxidative and reductive pathways of biogenic amine aldehydes may be implicated in and/or associated with the underlying mechanism(s) of action.

Differential mood changes following basal ganglia vs thalamic lesions.

Patients with computed tomographic scan-verified unilateral lesions in the basal ganglia or thalamus were examined for the presence of poststroke mood disorders. Patients with left-sided basal ganglia lesions (mainly in the head of the caudate nucleus) showed a significantly higher frequency and severity of depression, as compared with patients with right-sided basal ganglia or thalamic (left- or right-sided) lesions. Results suggest that damage to biogenic amine pathways and/or frontocaudate projections may play an important role in the modulation of mood.

Amine pathways and sleep regulation

The development of histofluorescence anatomical techniques has allowed a wide variety of direct new approaches to be applied to studies of the functions of the reticular formation. Many reticular nuclei and pathways, previously poorly understood, have now taken on a specific chemical identity. Thus, it has been possible to directly visualize constituent biogenic amine systems in the core of the brainstem and manipulate these by pharmacological, lesioning and stimulation procedures. Biochemical neuroanatomy has, therefore, provided the essential chemical dissections of neuronal systems as a basis for examining the individual roles of neurotransmitters in behavior. In sleep biology transmitter morphology has directly led to monoamine interaction theories of the entire vigilance continuum and has identified the substrates critical for pharmacological approaches to unravelling the roles of individual amine systems in different aspects of the sleep-waking states. Various of these studies as applied to sleep biology are reviewed in this paper.

Reaction of 2-arylazobenzimidazolium quaternary salts with amines

Different behaviors of aromatic and nonaromatic amines with respect to a change in the structure of the salt and variations in the reaction conditions were revealed in a study of the reaction of 2-arylazobenzimidazolium quaternary salts with amines. Aliphatic and secondary cyclic amines react at comparable rates via pathways involving cleavage of the azo group and replacement of the hydrogen in the para position relative to the azo group. The reaction with aromatic amines proceeds primarily via the amination pathway, and a methyl group in the meta position relative to the azo group facilitates replacement of the hydrogen atom significantly.