The tyramines: are they involved in the psychoses?

On the evidence that the administration of some antipsychotic drugs and d-amphetamine, separately and in combination, induced changes in the concentration of striatal p- and m-tyramine, it is proposed that the tyramines may possess a role in neural function. This function could be as neurotransmitters in specific neuronal systems or as synaptic activators.

Evidence for the presence of m-tyramine, p-tyramine, tryptamine, and phenylethylamine in the rat brain and several areas of the human brain.

Postmortem human brains have been obtained from four nonpsychiatric patients, aged 59-70 years. Regional analysis of the trace amines phenylethylamine, p-tyramine, m-tyramine, and tryptamine has indicated that the amines are distributed heterogeneously throughout the brain, but are most concentrated in the basal ganglia. Although the levels are very low, evidence obtained from animal studies has indicated that the trace amines have a very rapid turnover rate. Their presence in a brain synaptosomal fraction suggests a possible involvement in the process of neurotransmission. Postmortem changes in human brain amines are discussed in relation to those occurring postmortem in the rat brain, in which phenylethylamine, p-tyramine, and tryptamine have been shown to increase to levels greater than those prevailing in vivo.

Plasma phenylethylamine in schizophrenic patients.

Plasma samples were collected from 41 patients who met DSM-III criteria for schizophrenia and from 34 healthy controls. Phenylethylamine (PE) levels were determined using a gas chromatography-mass spectrometry negative chemical ionization method. PE was significantly higher in the schizophrenic patients compared with controls. There were no differences in PE between paranoid and nonparanoid patients. Plasma PE did not appear to be influenced by the severity of schizophrenic symptoms (rated by BPRS, SANS, and SAPS) or by the amount of dietary phenylalanine ingested within 24 hr of testing. Plasma PE did not correlate with current or past exposure to neuroleptic medication. It was not possible, however, to test individual patients during two periods when they were taking and not taking medication. Thus it is possible that neuroleptic exposure may have confounded the results. This study provides further evidence that PE excess may play a role in the etiology of schizophrenia but does not support previous studies which suggest that such an abnormality is limited to the paranoid subgroup.

Longitudinal effect of amitriptyline and fluoxetine treatment on plasma phenylacetic acid concentrations in depression.

Unconjugated (U-PAA), conjugated (C-PAA), and total phenylacetic acid (T-PAA) concentrations in blood plasma and monoamine oxidase (MAO) activity in platelets towards phenylethylamine (PE) were determined in 40 drug-free, depressed patients (23 melancholic, 17 nonmelancholic) from five psychiatric treatment centers, and in 34 normal healthy volunteers. No significant differences were found between controls and all depressed patients or between melancholic and nonmelancholic depressed patients. Treatment of the depressed patients with amitriptyline or fluoxetine over a 6-week period resulted in clinical improvement and in a significant increase in plasma PAA concentrations. A decline in the Beck and Hamilton rating scores during treatment correlated significantly with increases in the concentrations of unconjugated, conjugated, and total phenylacetic acid but not with MAO activity, which did not change during treatment. At each of the three assessment times, however, plasma PAA concentrations and psychiatric rating scores were not significantly correlated. Except for higher end-of-study T-PAA concentrations in the amitriptyline-treated subjects, no significant differences were found between the effects of the two drugs with regard to plasma phenylacetic acid levels, MAO activity, or rating scores.

Symptomatic and neuroprotective properties of the aliphatic propargylamines.

This short review describes the development of several families of aliphatic propargylamine drugs. The parent family--the aliphatic N-methylpropargylamines are potent, specific, irreversible MAO-B inhibitors, like R-deprenyl; but devoid of R-deprenyl's toxicity and amphetaminergic effects. In addition the parent drugs are potent antiapoptoic agents. Their desmethyl and further oxidized metabolites whilst devoid of MAO-B inhibitory properties of R-2HMP (our chosen drug candidate) are described along with the suggestion that this drug be developed for the treatment of several human neurodegenerative conditions.

Aliphatic propargylamines: potent, selective, irreversible monoamine oxidase B inhibitors.

A series of aliphatic propargylamine derivatives has been synthesized. Some of them possess highly potent, irreversible, selective, inhibitory activity toward monoamine oxidase B (MAO-B). The potency of the inhibitors is related to chain length and substitution of a hydrogen on the terminal carbon of the aliphatic chain. MAO inhibitory activity as assessed in vitro increased as the aliphatic carbon chain length increased. Substitution of a hydrogen by hydroxyl, carboxyl, or carbethoxyl groups at the aliphatic chain terminal or replacement of the methyl group on the nitrogen atom by an ethyl group considerably reduced the inhibitory activity. Stereospecific effects were observed with the R-(-)-enantiomer being 20-fold more active than the S-(+)-enantiomer. Inhibitors with relatively short carbon chain lengths (i.e. four to six carbons) were found to be more potent than those with longer chains in inhibiting brain MAO-B activity in vivo especially after oral administration. Chronic administration of low doses of the aliphatic propargylamines caused a slight cumulative inhibition of MAO-A activity in the mouse brain. These MAO-B inhibitors appear to be nontoxic, and they do not possess an amphetamine-like moiety in their structure as is the case for deprenyl. We expect that these aliphatic propargylamines may be useful in the treatment in certain neuropsychiatric disorders.

Regulation of aromatic L-amino acid decarboxylase in rat striatal synaptosomes: effects of dopamine receptor agonists and antagonists.

1. In this study we investigated the effects of dopamine receptor agonists and antagonists on rat striatal synaptosomal aromatic L-amino acid decarboxylase (AADC) activity. 2. The results show that 10(-5)-10(-7) M cis-flupenthixol increased the striatal synaptosomal AADC activity (by 25% to 57%) in a time-dependent manner. SCH 23390 and remoxipride alone had little or no effect on striatal synaptosomal AADC activity, but in combination they increased AADC activity by 20%, suggesting that the increases in striatal synaptosomal AADC activity occurred only after blockade of both dopamine D1 and D2 receptors. 3. Treatment with (+)-amphetamine and (+/-)-2-(N-phenylethyl-N-propyl)amino-5- hydroxytetralin hydrochloride ((+/-)-PPHT) produced a reduction of striatal synaptosomal AADC activity in a concentration- and time-dependent manner. SKF 38393 and (-)-quinpirole, however, exhibited no effect on striatal synaptosomal AADC activity, suggesting that only the mixed dopamine receptor agonists can reduce the AADC activity. Incubation with apomorphine at a concentration of 10(-4) M inhibited the AADC activity by 74% and this inhibition cannot be antagonized by SCH 23390, remoxipride or cis-flupenthixol, suggesting that apomorphine-induced inhibition of striatal synaptosomal AADC activity was not mediated by dopamine receptors. 4. cis-Flupenthixol can reverse the reduction of AADC activity induced by (+)-amphetamine and (+/-)-PPHT. The inhibition of AADC activity elicited by (+/-)-PPHT also can be reversed by SCH 23390 and remoxipride. 5. The inhibition of striatal synaptosomal AADC activity induced by (+/-)-PPHT is calcium-dependent and protein kinase C may play a role in the regulation of striatal AADC activity. 6. These studies show that striatal synaptosomal AADC activity is regulated by dopamine receptors and indicate that in vitro dopamine DI and D2 receptors have a synergistic effect in this regulation.

The effects of reserpine and 6-hydroxydopamine on the concentrations of some arylakylamines in rat brain.

1 The concentrations of p- and m-tyramine were measured in the caudate nucleus of the rat brain following subcutaneous injection of reserpine or intraventricular injection of 6-hydroxydopamine, beta-Phenylethylamine was analysed in the hypothalamus after reserpine. 2 Endogenous levels of p-tyramine and m-tyramine in the caudate nucleus, and beta-phenylethylamine in the hypothalamus were 8.02, 2.25 and 2.52 ng/g respectively. 3 Tyramine concentrations were reduced to less than 20% of control values one day after a reserpine injection of 1 or 10 mg/kg. A single dose of reserpine (0.4 mg/kg) significantly decreased the content of both tyramines in the caudate nucleus. The effects became apparent as early as 45 min after drug case of m-tyramine. 4 The hypothalamic content of beta-phenylethylamine was unaffected by reserpine. 5 Ten days after an intraventricular injection of 6-hydroxydopamine (250 mug), p- and m-tyramine concentrations in the caudate nucleus were significantly below control levels. 6 The results suggest that p- and m-tyramine may be stored by an intraneuronal reserpine-sensitive storage mechanism. Alternatively, the tyramines may replace some of the catecholamines from their storage granules and then be released as false transmitters by the nervous impulse. The observed changes in tyramine levels might also the fact that these amines may be metabolically related to another amine which is stored in reserpine-sensitive granules.

Effect of deuterium substitution on the disposition of intraperitoneal tryptamine.

To determine whether alpha,alpha-dideutero substitution in the side chain of the tryptamine molecule can exert primary isotope effects and enhance its bioavailability, equimolar mixtures of tryptamine (T) and either alpha,alpha-dideutero-tryptamine (alpha,alpha-[2H2]T) or beta,beta-dideutero-tryptamine (beta,beta-[2H2]T) were injected i.p. into rats. The amounts of these amines in the brain, liver and plasma were then measured at various times following the injection, and ratios between the deuterated T and T were computed. The ratio remained close to unity in plasma, but exceeded unity in the liver and brain when alpha,alpha-[2H2]T and T were injected; however, when beta,beta-[2H2]T and T were injected, the ratios were unity in all cases at all times. In the presence of a monoamine oxidase inhibitor, the relative enrichment of alpha,alpha-[2H2]T compared to T was reduced. It is concluded that alpha,alpha-dideutero substitution exerts a primary isotope effect during oxidative deamination so that much more of this amine penetrates into, and persists in, the brain.

Formation of beta-phenylethylamine from the antidepressant, beta-phenylethylhydrazine.

To determine whether the monoamine oxidase inhibitor phenelzine was metabolized in vivo to produce beta-phenylethylamine (PE) and p-hydroxy-beta-phenylethylamine [p-tyramine (pTA)], a deuterated analogue, alpha, alpha,, beta, beta-2H-phenelzine (d4-phenelzine) was synthesized and injected i.p. into rats. In the first experiment, rat striata from d4-phenelzine-treated rats were analyzed for the presence of d4-PE and d4-pTA at a time at which phenelzine was known to cause particularly large increases in striatal pTA. While d4-PE was found to be present in these rat striata at a concentration equivalent to the endogenous PE, no d4-pTA was present. The amounts of d4-PE produced at various times after the i.p. injection of 50 mg/kg d4-phenelzine were measured; at 1 hr post-injection, 371 +/- 60, 1295 +/- 682 and 1242 +/- 394 ng/g (mean +/- S.E.M.) d4-PE were present in whole brain, liver and kidney. Rat urine collected for a 24-hr period after this treatment contained (mean +/- S.E.M.) 88.5 +/- 14.0 micrograms d4-PE. These results clearly indicate that the antidepressant phenelzine was metabolized in vivo to produce the trace amine PE.

Effect of structural modification of alkyl N-propargylamines on the selective inhibition of monoamine oxidase B activity.

A series of alkyl N-methyl-propargylamine derivatives has been discovered recently to be very potent selective irreversible monoamine oxidase B inhibitors (MAO-B). In the present study, we used a simple compound in this series, namely N-2-butyl-N-methylpropargylamine.HCl (2-BuMP), as the basic structure to investigate the effect of structural modification on the effectiveness and selectivity of the inhibition of MAO activities. When the N-methyl group was replaced by a hydrogen atom, an ethyl group or a propargyl group, MAO inhibitory activity was abolished. The modification of the propargyl group, e.g. to 3-butynyl, N-cyanomethyl or to allyl groups, also destroyed the inhibitory activity. The potency of the inhibitors was related to the carbon chain length of the alkyl group as well as to the substitution of the alpha or the terminal carbon atoms. Substitution of hydroxyl, carboxyl or carboethoxyl groups on the terminal carbon of the alkyl chain drastically reduced the inhibitory activity. More potent MAO inhibitory activity was observed for molecules with a single methyl group substitution on the alpha carbon in comparison with those substituted with two hydrogen or two methyl groups. Other branched alkyl N-methylpropargylamines, e.g. N-methyl-N-(3-pentyl)propargylamine, appeared to be slightly less selective in the inhibition of MAO-B activity. Some of these alkyl propargylamine MAO-B inhibitors, which do not possess the amphetamine-like moiety of L-deprenyl, may have significant neuropsychopharmacological implications.

Effects of monoamine oxidase inhibitors on the acid metabolites of some trace amines and of dopamine in the rat striatum.

The effects of the administration of selective and non-selective inhibitors of monoamine oxidase (MAO) on the concentrations of three trace acid metabolites [phenylacetic acid (PAA); m-hydroxyphenylacetic acid (mHPAA); and p-hydroxyphenylacetic acid (pHPAA)] and of an acid metabolite of dopamine [3,4-dihydroxyphenylacetic acid (DOPAC)] in the rat striatum were determined. Administration of brofaromine (1-100 mg/kg, s.c.) a type AMAO inhibitor, dose-dependently decreased DOPAC and mHPAA levels. pHPAA levels were decreased by 100 mg/kg brofaromine, but PAA levels were unaffected. Doses of deprenyl of less than 100 mg/kg, i.p., had no effect on any of the acids, while 100 mg/kg decreased DOPAC, mHPAA and pHPAA but not PAA levels. Clorgyline, pargyline and tranylcypromine treatment decreased the levels of DOPAC, mHPAA and pHPAA but not PAA. Administration of alpha-monofluoromethyldopa, an inhibitor of aromatic amino acid decarboxylase, decreased the levels of all four acids. It was concluded that deamination of the respective parent amine by type A MAO is primarily responsible for the synthesis of DOPAC and mHPAA, but that another pathway contributes to pHPAA synthesis. It appears that either PAA arises predominantly independently from the actions of MAO or that is removal via transport or further metabolism regulates its concentration.

Potentiation of the biochemical effects of beta-phenylethylhydrazine by deuterium substitution.

The concentrations of dopamine (DA), m-tyramine (mTA), p-tyramine (pTA) and serotonin (5-HT) in the striata of rats 18 hr after the administration of three different doses (5, 50, or 100 mg/kg) of beta-phenylethylhydrazine (phenelzine, PEH) were measured. These concentrations were compared to those following the administration of the same doses of 1,1,2,2-tetradeutero-PEH (d4PEH). In general, PEH and d4PEH caused dose-dependent increases in the levels of mTA, pTA and 5-HT. The lowest dose of d4PEH caused greater increases than PEH in the levels of all four monoamines. The concentration of 5-HT was increased more by d4PEH than PEH at all three doses. The inhibition of mitochondrial MAO obtained from rat striatum by PEH or d4PEH in vitro revealed no differences. However, the inhibition of striatal MAO obtained from rats injected with d4PEH was found to be greater than that from rats injected with PEH. It was concluded that deuteration of PEH potentiates its ability to inhibit MAO following its administration to the rat by slowing its degradation in vivo.

Stereospecific deuterium substitution at the alpha-carbon position of dopamine and its effect on oxidative deamination catalyzed by MAO-A and MAO-B from different tissues.

Stereospecific replacement of deuterium in the alpha-carbon side chain position of dopamine (DA) was achieved by decarboxylation of L-3,4-dihydroxyphenylalanine (L-dopa) using hog kidney aromatic aminoacid decarboxylase. The S[alpha-2H1]DA enantiomer was obtained by decarboxylation of L-[alpha-2H1]dopa in H2O, while the R[alpha-2H1]DA enantiomer was obtained by decarboxylation of unsubstituted L-dopa in 2H2O. An inverse solvent isotope effect of L-dopa decarboxylation was observed in 2H2O. The deaminated aldehyde products of the four DA analogues, i.e. undeuterated DA, [alpha, alpha-2H2] DA, R[alpha-2H1]DA and S[alpha-2H1]DA, have been analyzed by the gas chromatography-mass spectrometry (GC-MS) method. It is evident that monoamine oxidase (MAO) catalyzes the stereochemical removal of only R-deuterium and that S-deuterium was maintained at the alpha-carbon atom of 3,4-dihydroxyphenylacetaldehyde. The steady-state kinetics of the oxidative deamination of undeuterated, [alpha, alpha-2H2], R[alpha-2H1], and S[alpha-2H1] dopamine were assessed by determination of the aldehyde products directly by high performance liquid chromatography (HPLC) using electrochemical detection (ECD). MAO-A from rat liver mitochondria (deprenyl-treated) and from human placenta, as well as MAO-B from rat liver (clorgyline-treated) and from human platelet were used in this study. The apparent isotope effects, i.e. (V/K)H/(V/K)D ratios of [alpha, alpha-2H2]DA and R[alpha-2H1]DA, were quite similar (2.34 and 3.13) with respect to both MAO-A and MAO-B. S[alpha-2H1]DA exhibited a slight secondary isotope effect. Formula: see text.

Interaction of biogenic amines with components of cigarette smoke. Formation of cyanomethylamine derivatives.

A reaction of the biogenic amines 5-hydroxytryptamine, dopamine, histamine, p-tyramine, beta-phenylethylamine and tryptamine with components of cigarette smoke was observed. The adducts formed from 5-hydroxytryptamine and beta-phenylethylamine were purified by chromatographic procedures and identified by high resolution mass spectrometry. The structures of some of these compounds were established as cyanomethylamine derivatives, i.e. RCH2CH2NHCH2CN. In the case of 5-hydroxytryptamine, a cyanomethyl-beta-1,2,3,4-tetrahydrocarboline product formed via a Pictet-Spengler condensation reaction was isolated. The mass spectra of such adducts and their fragment ions were observed to be identical to those of chemically synthesized cyanomethylamines. Both formaldehyde and cyanide, which are known to be present in cigarette smoke, were involved in the reaction with the primary amines. The reaction was time dependent and was enhanced by an increase in temperature or by incubation under alkaline conditions. Cyanomethyl adduct formation was increased when smoke from cigarettes with higher tar and nicotine content was used. When the amines were incubated with human saliva obtained after cigarette smoking, cyanomethylamine products were readily detected.

Neurochemical, neuroprotective and neurorescue effects of aliphatic N-methylpropargylamines; new MAO-B inhibitors without amphetamine-like properties.

A series of aliphatic N-methylpropargylamine MAO-B inhibitors have been synthesized and their structural and functional relationships have been investigated. 2-Hexyl-N-methylpropargylamine (2-HxMP), for example, has been found to be a highly potent, irreversible, selective, MAO-B inhibitor both in vitro and in vivo. The R-(-)-enantiomers are much more active than the S-(+)-enantiomers at inhibiting MAO-B activity. Some of these compounds protect mouse nigrostriatal dopamine neurons against the neurotoxin MPTP and the mouse hippocampal noradrenergic system against the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). They rescue hippocampal neurons after damage induced by ischemia and kainic acid treatment, as well as motoneurons in young mice following facial nerve axotomy. Such rescue effects are, interestingly, unrelated to inhibition of MAO-B activity. Some of the aliphatic propargylamines enhance the survival of neuroblastoma cells co-cultured with astrocytes following serum depletion. They stimulate the expression of AADC mRNA and inhibit GFAP mRNA expression. They do not possess amphetamine-like properties and exhibit no effect on noradrenaline or dopamine uptake nor do they increase hypertensive effects in the tyramine pressor test. Unlike R(-)-deprenyl, 2-HxMP does not potentiate dopamine toxicity in vitro. These new MAO-B inhibitors may possess significant chemotherapeutic implications for certain psychiatric and neurodegenerative disorders.

Inhibition of monoamine oxidases by haloperidol and its metabolites: pharmacological implications for the chemotherapy of schizophrenia.

The effect of haloperidol and its metabolites on human platelet monoamine oxidase B (MAO-B) and human placenta monoamine oxidase A (MAO-A) in vitro has been investigated. We found that 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (HP+), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine (HTP) and 4-chlorophenyl-1,2,3,6-tetrahydropyridine (CPTP) are potent inhibitors of MAO. HP+ appeared to be a reversible, uncompetitive and selective MAO-B inhibitor with a Ki of 0.83 microM. HTP was found to be an irreversible, uncompetitive and selective MAO-B inhibitor (Ki of 1.84 microM). CPTP inhibits both MAO-A and MAO-B. Some other haloperidol metabolites, i.e. 4-(4-chlorophenyl)-4-hydroxypyridine (CPHP), 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-1,2,3,6- tetrahydropyridine N-oxide (HTPNO) and reduced haloperidol (RHAL), do not inhibit MAO to any appreciable degree at concentrations up to 100 microM. The results suggest that haloperidol metabolites may contribute to the reduction of platelet MAO-B activity in schizophrenic patients undergoing neuroleptic chemotherapy. An examination of the literature reveals that schizophrenic patients with low platelet MAO activity exhibit a strong association with the use of haloperidol. Other possible pharmacological implications of the inhibition of MAO activity are discussed.

Potentiation of the behavioural effects of the antidepressant phenelzine by deuterium substitution.

Phenelzine in the rat induced biphasic behavioural stimulation, which was profoundly potentiated by deuterium substitution. Doses of 12.5 or 25.0 mg/kg phenelzine had little or no effect on spontaneous activity, whereas the same doses of deuterated phenelzine produced hyperactivity, wet-dog shakes, forepaw padding, splayed hind limbs, backward walking, sniffing and stereotyped grooming 2-12 h after injection. Similarly, the behavioural response induced by 50.0 mg/kg phenelzine was strongly potentiated by deuterium substitution. It appears likely that the increased behavioural response induced by deuterated phenelzine may be due to its greater potency as a monoamine oxidase inhibitor compared to undeuterated phenelzine. Since phenelzine is an antidepressant that is particularly efficacious in the treatment of severe anxiety, a deuterated analogue of the drug seems likely to be clinically useful.

A behavioural and neurochemical analysis of chronic and selective monoamine oxidase inhibition.

The effects of clorgyline were compared with the effects of (-)-deprenyl using measures of rewarding hypothalamic self-stimulation, regional monoamine metabolism and monoamine oxidase activity. Male Wistar rats trained to self-stimulate at half-maximal rates with unilateral bipolar lateral hypothalamic electrodes on a continuous reinforcement schedule were implanted subcutaneously with osmotic minipumps which delivered 1 mg X kg-1 drug per day or vehicle for 13 days. A response rate/stimulation frequency (reward summation) function was determined the day before minipump implantation and on days 5 and 13 of drug administration. Only clorgyline induced a shift to the left in the reward summation function at 5 and 13 days, indicating enhancement of reinforcement. Clonidine (50 micrograms X kg-1 IP) probe tests were run on days 2 and 10 to determine the sensitivity of alpha 2-noradrenaline receptors. Clorgyline induced an attenuation of the clonidine response on day 10 relative to day 2. The other groups exhibited no change in response to clonidine. Clorgyline also induced a progressive increase in self-stimulation rates; this effect was not observed with the other groups. The clorgyline effects were accompanied by an increase in regional brain levels of dopamine, noradrenaline and 5-hydroxytryptamine and a reduction of their acid metabolites. Clorgyline selectively inhibited type A monoamine oxidase, whereas (-)-deprenyl selectively inhibited type B monoamine oxidase.

Aliphatic N-methylpropargylamines as potential neurorescue agents.

Several clinical investigations have indicated that R-deprenyl, a typical monoamine oxidas B inhibitor, delays the progression of Parkinson's and Alzheimer's disease. A number of aliphatic N-methylpropargylamines, such as R-2-hexyl-N-methylpropargylamines (R-2HxMP), have been found to be highly potent, irreversible, selective, MAO-B inhibitors both in vitro and in vivo. These aliphatic propargylamines do not affect noradrenaline of dopamine uptake and are chemically without an amphetamine moiety and therefore do not exhibit any amphetamine-like effects. They are capable of protecting mouse striatal dopamine neurons against MPTP-induced toxicity in the caudate, against MK-801-induced apoptosis in the retrosplenial cortex and against DSP-4-induced depletion of naradrenergic axons. They rescue hippocampal neurons in rodents following kainate-induced neuronal damage. They block the expression of heat shock protein (HSP70) and delayed c-Fos expression in hippocampal CA1 region as elicited by kainate. Confocal microscopy also revealed prevention of neuronal damage in hippocampal slices under hypoxia-hypoglycemia conditions. Aliphatic N-methylpropargylamines may be useful in the treatment of neurodegenerative disorders. The mechanism and site of action of the neurorescue effect of these propargylamines, however, remains to be established.