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PubMed1982

Serotonin receptor blockade potentiates behavioural effects of beta-phenylethylamine.

The 5-hydroxytryptamine (5HT) receptor blocker, methysergide (10 mg/kg), was found to potentiate the behavioural effects of beta-phenylethylamine (PEA) (at doses between 20 and 60 mg/kg) on food reinforced schedule-maintained behaviour in two separate experiments involving a fixed interval 2 min schedule and a fixed ratio 20 schedule. Potentiation caused a parallel shift to the left in the log dose response curve for suppression of responding induced by phenylethylamine, and was observed in both male and female rats. These data contrast with recent reports indicating that inhibition of functioning of 5HT systems blocks the effects of phenylethylamine in inducing the "Serotonin behavioural syndrome" (Sloviter et al., 1980a: Dourish, 1981). However, the potentiation reported here is compatible with frequent reports indicating that behavioural effects of amphetamine (alpha-methyl-PEA) can be potentiated by reduction in 5HT functioning and are thus compatible with the hypothesis that phenylethylamine is a potential "endogenous amphetamine".

Animals↗

PubMed1991

Differences in imidazoline and phenylethylamine alpha-adrenergic agonists: comparison of binding affinity and phosphoinositide response.

The imidazoline class of compounds, reported to be partial agonists at alpha 1 adrenoceptors, were compared with phenylethylamines for their ability to displace the binding of [3H]prazosin and to stimulate hydrolysis of phosphoinositides in the cerebral cortex of the rat. Both classes of alpha adrenoceptor compounds exhibited two sites of interaction with binding sites for [3H]prazosin in 30 mM Tris buffer. In a Na+ containing ionic buffer, the competition by phenylethylamines for [3H]prazosin sites shifted to a one-site best-fit, while imidazolines retained their two-site best-fit. Phenylethylamines stimulated hydrolysis of phosphoinositides in a dose-dependent manner, with ED50 values that correlated with Kd values from competition curves. In contrast, imidazolines were not potent or efficacious at stimulating hydrolysis of phosphoinositides and the binding affinities did not correlate with the ED50 values. The alpha 1 adrenoceptor antagonist, prazosin potently inhibited phenylethylamine, but not imidazoline-stimulated hydrolysis of phosphoinositides. Dose-response curves to the imidazoline, oxymetazoline, in the presence and absence of maximally stimulating concentrations of norepinephrine, indicated that oxymetazoline caused a dose-dependent inhibition of norepinephrine-stimulated hydrolysis of phosphoinositide. The inhibition of norepinephrine-stimulated hydrolysis of phosphoinositides was evident up to 100 microM, at which point oxymetazoline elicited hydrolysis of phosphoinositides through a non-alpha 1 adrenoceptor-mediated mechanism. These data indicate that imidazolines act primarily as antagonists at the alpha 1 adrenoceptor, coupled to hydrolysis of phosphoinositide and stimulate the hydrolysis of phosphoinositide through a non-alpha 1 adrenoceptor mechanism.

Animals↗

PubMed1985

Effects of d-amphetamine and of beta-phenylethylamine on fixed interval responding maintained by self-regulated lateral hypothalamic stimulation in rats.

d-Amphetamine sulphate (0.25-4.0 mg/kg) and beta-phenylethylamine hydrochloride (1.25-50 mg/kg) respectively were administered IP to two groups of rats (R1-R4 and R5-R8 respectively) responding on a fixed interval (FI) schedule (R1-R4 FI 60 sec, R5-R8 FI 30 sec) of electrical hypothalamic stimulation. The duration of each train of stimulation was controlled by the duration of each lever press that initiated stimulation. Under these conditions administration of d-amphetamine resulted in a marked increase in overall response rates on the FI 60 sec schedule. This effect was significant at 1, 2 and 4 mg/kg. d-Amphetamine had not significant effect on the duration of hypothalamic stimulation or on the duration of responses occurring during the FI. Administration of beta-phenylethylamine resulted in a decrease in overall response rates on the FI 30 sec schedule. This effect was significant at 50 mg/kg. beta-Phenylethylamine increased the duration of responses occurring during the FI, this effect being significant at 25 and 50 mg/kg, but had no significant effect on the duration of hypothalamic stimulation. These results indicate that the systemic effects of d-amphetamine on response rate, and of beta-phenylethylamine on both response rate and response duration, are dissociable from changes in the self-regulated duration of lateral hypothalamic stimulation.

Animals↗

PubMed1991

Effect of dietary phenylalanine on the plasma concentrations of phenylalanine, phenylethylamine and phenylacetic acid in healthy volunteers.

1. Phenylethylamine has been proposed as a neuromodulator in several psychiatric and other brain disorders, and its concentration and that of its major metabolite, phenylacetic acid, in plasma may prove useful as state or trait markers in diagnosis, treatment or in the elucidation of biochemical mechanisms of these disorders. 2. The effect of dietary phenylalanine intake and changes in dietary phenylalanine intake on the plasma concentrations and changes in plasma concentrations, respectively, of phenylalanine, phenylethylamine and unconjugated and conjugated phenylacetic acid have been investigated. 3. Dietary phenylalanine affects the concentration of plasma phenylalanine on the following day, but has no effect on phenylethylamine or phenylacetic acid concentrations. Thus single measurements per subject of phenylethylamine or phenylacetic acid do not need to take dietary factors into account. 4. Changes in dietary phenylalanine (whether in absolute amount or in the proportion of phenylalanine in the diet) are significantly correlated with changes in unconjugated phenylacetic acid. Therefore, in longitudinal studies, dietary factors should be taken into account.

Adult↗

PubMed2001

Apomorphine, dopamine and phenylethylamine reduce the proportion of phosphorylated insulin receptor substrate 1.

We tested the ability of dopamine, apomorphine, phenylethylamine and pergolide to inhibit the proliferation of fetal calf serum-stimulated human breast cancer (MCF)-7 cells. While the first three compounds were able to block the proliferation of MCF-7 cells, pergolide failed to do so (up to 100 microM). The inhibitory effect of dopamine, apomorphine and phenylethylamine was also evident in serum-starved insulin-stimulated MCF-7 cells. Apomorphine also inhibited the proliferation of the human oestrogen receptor-negative breast cancer (MDA-MB231) and prostate carcinoma (LNCaP) cell lines. In a second set of experiments, we measured the ability of dopamine, apomorphine, phenylethylamine and pergolide to inhibit the phosphorylation (or increase the dephosphorylation) of the insulin receptor substrate (IRS)-1, a major intracellular substrate of the insulin-like growth factor (IGF)-1 receptor. Dopamine, apomorphine and phenylethylamine all reduced to zero the level of phosphorylated IRS-1 with potencies ranging between 0.01 and 1 microM. Finally, we found that fibroblasts from IRS-1 null (-/-) mice were less sensitive to the anti-proliferative effect of apomorphine compared to fibroblasts from wild type-mice, suggesting that the inhibition of IRS-1 phosphorylation by apomorphine is an important aspect of the activity of this compound.

Apomorphine↗

PubMed2003

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 micro M and for 4-methoxybenzaldehyde it was 0.86 micro 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 micro 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 micro 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.

Animals↗

PubMedDate not supplied

Presence of phenylethylamine in hallucinogenic Psilocybe mushroom: possible role in adverse reactions.

The use of mushrooms containing the hallucinogenic substance psilocybin for intentional intoxication is relatively common. Occasionally, this results in adverse reactions with typical tachycardia that is not evidently caused by psilocybin. This study demonstrates the presence of phenylethylamine in the species Psilocybe semilanceata using gas chromatography-mass spectrometry and shows that the amount of this substance may vary much more than that of psilocybin. The highest amount of phenylethylamine (146 microg/g wet weight) was observed in mushrooms from a case of three young men hospitalized because of adverse reactions. Comparison of the symptoms observed in clinical cases of magic mushroom intoxication with those after intake of pure psilocybin or phenylethylamine suggests that phenylethylamine might have a role in the development of adverse reactions to Psilocybe mushroom intake.

Adult↗

PubMed2004

Enzymatic oxidation of 2-phenylethylamine to phenylacetic acid and 2-phenylethanol with special reference to the metabolism of its intermediate phenylacetaldehyde.

2-phenylethylamine is an endogenous constituent of the human brain and is implicated in cerebral transmission. This bioactive amine is also present in certain foodstuffs such as chocolate, cheese and wine and may cause undesirable side effects in susceptible individuals. Metabolism of 2-phenylethylamine to phenylacetaldehyde is catalysed by monoamine oxidase B but the oxidation to its acid is usually ascribed to aldehyde dehydrogenase and the contribution of aldehyde oxidase and xanthine oxidase, if any, is ignored. The objective of this study was to elucidate the role of the molybdenum hydroxylases, aldehyde oxidase and xanthine oxidase, in the metabolism of phenylacetaldehyde derived from its parent biogenic amine. Treatments of 2-phenylethylamine with monoamine oxidase were carried out for the production of phenylacetaldehyde, as well as treatments of synthetic or enzymatic-generated phenylacetaldehyde with aldehyde oxidase, xanthine oxidase and aldehyde dehydrogenase. The results indicated that phenylacetaldehyde is metabolised mainly to phenylacetic acid with lower concentrations of 2-phenylethanol by all three oxidising enzymes. Aldehyde dehydrogenase was the predominant enzyme involved in phenylacetaldehyde oxidation and thus it has a major role in 2-phenylethylamine metabolism with aldehyde oxidase playing a less prominent role. Xanthine oxidase does not contribute to the oxidation of phenylacetaldehyde due to low amounts being present in guinea pig. Thus aldehyde dehydrogenase is not the only enzyme oxidising xenobiotic and endobiotic aldehydes and the role of aldehyde oxidase in such reactions should not be ignored.

Acetaldehyde↗

PubMed1982

Precursors and metabolites of phenylethylamine, m and p-tyramine and tryptamine in human lumbar and cisternal cerebrospinal fluid.

Phenylacetic acid, p-hydroxyphenylacetic acid, m-hydroxyphenylacetic acid, phenylalanine, indoleacetic acid, 5-hydroxyindoleacetic acid and tryptophan were measured in lumbar and cisternal cerebrospinal fluid (CSF) taken during pneumoencephalography. The data suggest that the concentration of the acid metabolites of the trace amines tryptamine, phenylethylamine, p-tyramine and m-tyramine in lumbar CSF are influenced by the system that transports these acids out of CSF. In cisternal CSF this mechanism does not operate and more information can be obtained on the metabolism of the parent amines in the CNS. Our data indicate that (1) m-tyramine is relatively unimportant quantitatively (2) the rate of metabolism of phenylethylamine in human brain is similar to that of 5-hydroxytryptamine (3) the most important variable controlling the synthesis of phenylethylamine is the activity of aromatic amino acid decarboxylase (4) p-tyramine is synthesised at about half the rate of phenylethylamine and is thus quantitatively important in metabolic terms.

Adolescent↗

PubMed1975

Metabolism distribution, and disappearance of injected beta-phenylethylamine in the rat.

In the absence of a monoamine oxidase inhibitor, the bulk of intravenously injected radioactively labelled beta-phenylethylamine was oxidized to phenylacetic acid. In the presence of pargyline, most of the label in tissues remained as unchanged phenylethylamine; small amounts of labelled phenylethanolamine, tyramine and octopamine were also identified. After intravenous injection of [14-C]phenylalanine, only very small amounts of [14-C] phenylethylamine could be located in urine and faeces. Beta-Phenylethylamine became concentrated in all tissues, including brain, following intravenous introduction both in the presence and absence of pargyline. Its clearance from these tissues and from brain regions was very fast.

Animals↗

PubMed1983

Effects of chronic D-amphetamine and phenylethylamine on the concentrations of neurotransmitter amino acids in the rat brain.

Rats were treated acutely and chronically with D-amphetamine or phenylethylamine. Following the treatments, the concentrations of amino acids in the hypothalamus and caudate nucleus were measured from prederivatized tissue extracts using reversed phase high pressure liquid chromatography with fluorescence detection. Acute amphetamine slightly decreased the caudate glutamine concentration, and chronic treatment for 10 days increased caudate aspartate content. Chronic phenylethylamine enhanced the taurine content, both in caudate and hypothalamus. No significant changes were observed in the concentrations of glutamate, GABA or alanine. The results indicate that these two stimulants can modify the brain metabolism of certain neuroactive amino acids in addition to the metabolism of catecholamines. The specific effect of chronic phenylethylamine on taurine concentration suggests an adaptive response of taurine-containing cells to repeated administrations of phenylethylamine.

Amino Acids↗

PubMedDate not supplied

Metabolism of 2-phenylethylamine to phenylacetic acid, via the intermediate phenylacetaldehyde, by freshly prepared and cryopreserved guinea pig liver slices.

BACKGROUND: 2-Phenylethylamine is an endogenous amine, which acts as a neuromodulator of dopaminergic responses. Exogenous 2-phenylethylamine is found in certain foodstuffs and may cause toxic side-effects in susceptible individuals. MATERIALS AND METHODS: The present investigation examined the metabolism of 2-phenylethylamine to phenylacetic acid, via phenylacetaldehyde, in freshly prepared and cryopreserved liver slices. Additionally, it compared the relative contribution of aldehyde oxidase, xanthine oxidase and aldehyde dehydrogenase by using specific inhibitors for each oxidizing enzyme. RESULTS: In freshly prepared and cryopreserved liver slices, phenylacetic acid was the main metabolite of 2-phenylethalamine. In freshly prepared liver slices, phenylacetic acid was completely inhibited by disulfiram (inhibitor of aldehyde dehydrogenase), whereas isovanillin (inhibitor of aldehyde oxidase) inhibited acid formation to a lesser extent and allopurinol (inhibitor of xanthine oxidase) had no effect. In cryopreserved liver slices, isovanillin inhibited phenylacetic acid by 85%, whereas disulfiram inhibited acid formation to a lesser extent and allopurinol had no effect. CONCLUSION: In liver slices, 2-phenylethylamine is rapidly oxidized to phenylacetic acid, via phenylacetaldehyde, by aldehyde dehydrogenase and aldehyde oxidase with no contribution from xanthine oxidase.

Acetaldehyde↗

PubMed1989

Conformational and steric aspects of phenylethanolamine and phenylethylamine analogues as substrates or inhibitors of phenylethanolamine N-methyltransferase.

The conformational and steric aspects of binding to phenylethanolamine N-methyltransferase (PNMT; EC 2.1.1.28) for phenylethanolamine substrates and phenylethylamine inhibitors were probed with three conformationally defined analogues (11, 12, and 13) of phenylethylamine (1) and phenylethanolamine (6) containing the benzobicyclo[3.2.1]octane skeleton. The 2-aminotetralin (2AT) moiety in conformationally defined analogues 11, 12, and 13 exists in a half-chair conformation with an equatorial amino group. Although conformationally restricted phenylethylamine analogue 2AT (3, Ki = 6.8 microM) and conformationally restricted phenylethanolamine analogues (cis)- and (trans)-2-amino-1-tetralol (9, Km = 22 microM; Vmax = 0.15; 100 X Vmax/Km = 0.68; 10, Ki = 9.4 microM) are good ligands for PNMT, none of the analogues 11, 12, and 13 showed activity as a substrate of PNMT. The fact that 11 (Ki = 206 microM) is more potent than analogues 4 (Ki = 1296 microM) and 5 (Ki = 479 microM), with a half-boat 2AT moiety, suggests that PNMT preferentially binds the half-chair conformation of 2AT at the active site. This is consistent with previous findings that a fully extended conformation for the aminoethyl side chain of phenylethylamine inhibitors is optimal for PNMT binding. The reduced activity of 11, 12 (Ki = 1246 microM), and 13 (Ki = 3000 microM), compared with 2AT and (cis)- and (trans)-2-amino-1-tetralol (9 and 10) is consistent with a negative steric interference from the extra ethano bridge in 11, 12, and 13. The results from 11, 12, and 13, combined with previous findings, suggest that PNMT interacts better with relatively planar ligands.

2-Hydroxyphenethylamine↗

PubMed1978

Preliminary studies of the sodium borohydride stabilizable binding of phenylethylamine and tyramine to brain preparations.

The borohydride stabilizable binding of 2-phenylethylamine and p-tyramine to mouse brain homogenates was compared to that of tryptamine and of serotonin. The highest binding was found to be that of tryptamine, followed by that of serotonin, tyramine, and phenylethylamine. The stabilizable binding of phenylethylamine to calf midbrain (including corpus striatum) homogenates and synaptic membranes was decreased by dopamine; this amine and D-amphetamine also decreased the stabilizable binding of tyramine to rat brain homogenates. The subsynaptosomal distribution of the binding of phenylethylamine to synaptic calf midbrain fractions was also investigated. The highest binding capacity was found in the 0.8 M fraction, rich in myelin.

Animals↗

PubMed2002

Increased urine phenylethylamine after methylphenidate treatment in children with ADHD.

The urine levels of beta-phenylethylamine, 3-methoxy-4-hydroxyphenyl glycol, homovanillic acid, and 5-hydroxyindoleacetic acid were measured to clarify the neurochemical mechanism in attention deficit hyperactivity disorder. beta-Phenylethylamine levels were significantly lower in attention deficit hyperactivity disorder individuals (n = 37) than in controls (n = 21). The 22 children with attention deficit hyperactivity disorder were treated with methylphenidate, and they were further divided into methylphenidate responders (n = 18) and nonresponders (n = 4). beta-Phenylethylamine levels significantly increased after methylphenidate therapy in responders, whereas they did not increase in nonresponders.

Attention Deficit Disorder with Hyperactivity↗

PubMed1976

Characterisation of the mechanisms for hyperactivity induction from the nucleus accumbens by phenylethylamine derivatives.

A wide variety of phenylethylamine derivatives were injected bilaterally into the nucleus accumbens of rat following a nialamide pretreatment and hyperactivity was recorded. 2-Phenylethylamine was shown to induce a low intensity hyperactivity but the introduction of hydroxyl functions on to the phenyl ring at the 3- and/or 4-positions enhanced activity and m- and p-tyramine and dopamine each caused marked hyperactivity in the 3.4-25 mug dosage range. Methylation of one hydroxyl function reduced activity (3-methoxy-4-hydroxy- and 3-hydroxy-4-methoxy-phenylethylamine); 2(3,4-methylenedioxyphenyl) ethylamine was inactive. Agents with substitution of the side chain, such as noradreline, d-amphetamine and alpha-methyldopamine, were all shown to induce marked hyperactivity at doses of 1.6-25 mug. Alterations in the chain length markedly reduced activity (4-(3,4-dihydroxyphenyl) butylamine, 3,4-dihydroxybenzylamine). A variety of N-substituted compounds were shown to be potent inducers of hyperactivity from the nucleus accumbens (adrenaline, epinine, N-ethyldopamine, N-isopropyl-dopamine, isoprenaline) (0.2-25 mug). However, N-methyl-N-isopropyldopamine showed only weak activity and N,N-dimethyldopamine was inactive. All hyperactivity effects were shown to be dose-dependent. The hyperactivities induced by dopamine, noradrenaline and isoprenaline were each inhibited in a dose-dependent manner by subsequent injections of fluphenazine (1.25-25 mug) into the nucleus accumbens, although no reductions were recorded following similar injections of saline, solvent, 2% procaine, 50 mug propranolol or 50 mug piperoxan.

Animals↗

PubMed1976

Comparison of behavior maintained by infusions of eight phenylethylamines in baboons.

Doses of eight phenylethylamines were substituted for cocaine on a drug-maintained behavior baseline in baboons. Intravenous infusions of drug were contingent upon completion of 160 lever presses (a 160-response fixed-ratio schedule; FR 160). A 3-h time-out period followed each infusion, permitting a maximum of 8 infusions per day. Fenfluramine was the only drug that did not maintain self-infusion performance at any dose tested. d-Amphetamine was approximately 10 times more potent than phentermine, phenmetrazine or diethylpropion, and 20 to 30 times more potent than methylenedioxyamphetamine (MDA), clortermine or chlorphentermine, in maintaining self-infusion behavior. Some doses of d-amphetamine and phentermine produced a cyclic pattern of drug intake over days. Increasing self-infused doses of all drugs produced a substantial suppression of concurrent food-maintained behavior. There was no clear relation between the potency of the phenylethylamines in maintaining self-infusion performance and the potency in suppressing food-maintained behavior which indicates that different mechanisms may underlie the two effects. Examination of chemical structures indicates that substitution on the phenyl ring may decrease the potency of phenylethylamines in maintaining self-infusion behavior.

3,4-Methylenedioxyamphetamine↗

PubMed1978

Amphetamine and 2-phenylethylamine in post-mortem Parkinsonian brain after (-)deprenyl administration.

Deprenyl is an inhibitor of monoamine oxidase type B, the enzyme responsible for 2-phenylethylamine oxidation, and is used in conjunction with L-Dopa therapy in Parkinson's disease. Post-mortem studies in human brain tissue have shown that after (-)deprenyl administration to parkinsonian patients amphetamine is present in concentrations up to 56 ng/g. It also could be shown that phenylethylamine concentrations are substantially increased in such patients. Phenylethylamine and amphetamine have been investigated using a gas chromatographic technique.

Amphetamines↗