Effects of 3,N,N′-trimethyl-2-phenyl-1,4-piperazine diastereomers on monoamine uptake and monoamine oxidase in rat brain

Summary The diastereomers of 3,N,N-trimethyl-2-phenyl-1,4-piperazine dihydrochloride (TPP) were tested for their effects on NA, DA and 5-HT uptake in synaptosomes prepared from hypothalamus, corpus striatum, and frontal cortex, respectively. The diastereomers differed with respect to their inhibitory properties. (2R, 3R)-TPP was more potent than the other diastereomers on NA and DA uptake, whereas (2S, 3S)-TPP was least potent. In contrast, the (2S, 3S)- and (2 S, 3R)-diastereomers of TPP were more potent than (2R, 3R)- and (2R, 3S)-TPP as inhibitors of 5-HT uptake. None of the diastereomers affected monoamine oxidase activity. The findings show that the diastereomers of TPP interact stereoselectively with neuronal mechanisms for monoamine uptake, and that the (S)-configuration at the 2 carbon is important for inhibitory actions of TPP on 5-HT uptake.     

N‐methyl,N‐propargyl‐2‐phenylethylamine (MPPE), an analog of deprenyl,increases neuronal cell survival in thiamin deficiency encephalopathy

Wernicke encephalopathy (WE) is a neurological disorder attributable to thiamin deficiency (TD). Severe TD, in humans and animals, results in highly selective lesions with a symmetrical distribution in brain regions including the mammillary bodies, thalamus, inferior colliculi, periaqueductal and periventricular regions, and inferior olivary nuclei. Experimental TD in the rat provides a robust and reproducible model that allows investigations of mechanisms underlying both apoptotic and necrotic neuronal death. (‐)‐Deprenyl (DEP), a selective monoamine oxidase B (MAO‐B) inhibitor, has been reported to be clinically effective in the treatment of neurodegenerative disorders and to have neuroprotective and/or neurorescue properties in a variety of ex vivo and in vitro paradigms, including experimental TD. Because the metabolites of DEP, amphetamine, and methamphetamine may have adverse behavioral effects, a DEP analog, N‐methyl,N‐propargyl‐2‐phenylethylamine (MPPE) that is not metabolized to amphetamine or methamphetamine was examined in the present studies. Results showed that TD rats treated with MPPE had significantly increased neuronal cell counts compared to vehicle‐treated TD rats. MPPE, like DEP, also significantly decreased the density of reactive astrocytes and the infiltration of microglia/macrophages. Chronic treatment with DEP or MPPE resulted in significant inhibition of MAO‐A and MAO‐B activity compared to VEH‐treated animals. Thus, MPPE, an inhibitor of MAO activity, was shown to be neuroprotective in the TD model of neuronal cell death. Drug Dev. Res. 51:244–252, 2000. © 2001 Wiley‐Liss, Inc.     

COMPARISON OF THE ANORECTIC AND MOTOR ACTIVITY EFFECTS OF SOME AMINOINDANES, 2-AMINOTETRALIN AND AMPHETAMINE IN THE RAT

1. The anorectic and motor activity effects of 1-aminoindane, 2-aminoindane, some N-substituted 2-aminoindanes,2-aminotetralin, amphetamine and fenfluramine were determined in rats. 2. The two compounds with structures most like the extended conformation of amphetamine, 2-aminotetralin and 2-aminoindane, were potent anorectics. At dosages which halved the intake of food over 1 h, amphetamine increased motor activity, 2-aminotetralin had no effect, and 2-aminoindane reduced motor activity.’ 3. Both the anorectic and central stimulant actions of 2-aminoindane were absent in N-ethyl- and N-isopropyl-2-aminoindane. 4. 1-Aminoindane, whose structure is like the folded conformation of amphetamine, produced a small anorectic effect and depressed motor activity.     

Kinetic evaluation of platelet monoamine oxidase following relaxation in chronic anxiety

ABSTRACT - The effect of relaxation training, utilizing EMG biofeedback, on platelet monoamine oxidase (MAO) activity was examined in patients with a history of chronic anxiety. Anxiety scores and MAO activity were significantly lowered after 4 weeks of therapy. Kinetic studies, using phenylethylamine as substrate, indicated a significant increase of the K_m constant while the V. showed no significant or consistent variation. It is thought that this phenomenon represents an adaptive response by the individual to maintain a homeostatic level of the biogenic amines.     

Cross-cultural study of a biochemical abnormality in paranoid schizophrenia

We studied 24-hour urinary excretion of phenylethylamine (PEA) and creatinine in 50 schizophrenic (39 paranoid and 11 nonparanoid) and 19 nonpsychiatric patients from Bombay, India. Methods for diagnosis, clinical assessment, and 24-hour urine collection were identical to those used in an earlier study done in a Washington, D.C. hospital. Clinical evaluations were done in Bombay, while urinary PEA and creatinine estimations were performed at NIMH, Washington, without knowledge of the subjects' identity. Paranoid schizophrenic patients had significantly greater 24-hour urinary excretion of PEA than both nonparanoid schizophrenic patients and nonpsychiatric controls. The mean amount of PEA per g creatinine in urine was also highest for paranoid schizophrenic patients. Our findings provide cross-cultural support to the possibility of abnormal PEA metabolism in at least some patients with paranoid schizophrenia.     

Analysis and the effects of some drugs on the metabolism of phenylethylamine and phenylacetic acid

1. Phenylethylamine has been reliably measured using radioenzymatic, gas Chromatographic, mass spectromatic and gas Chromatographie — mass spectrometric methods.

2. Phenylacetic acid has been measured using gas Chromatographic and gas chromatographicmass spectrometric methods.

3. Phenylethylamine concentrations are increased primarily by phenylalanine, its amino acid precursor and by such monoamine oxidase inhibitors as L-deprenyl and pargyline.

4. Phenylethylamine administration influences other neurotransmitters such as dopamine, norepineph rine and 5-hydroxytryptamine. It also effects the tyramines and possibly tryptamine.     

A cocktail of synthetic stimulants found in a dietary supplement associated with serious adverse events

Food supplements are regularly found to contain pharmacologically active substances. Recently, the food supplement Dexaprine was removed from the Dutch market because it was associated with severe adverse events. Reports to the Dutch Poisons Information Center (DPIC) showed that ingestion of as little as half a tablet caused several cases of nausea, agitation, tachycardia, and palpitations and even one case of cardiac arrest. The remaining tablets of four patients were sent in by different healthcare professionals. Analysis by ultra‐performance liquid chromatography quadrupole time of flight mass‐spectrometry (UPLC–QTOF‐MS) confirmed the presence of synephrine, oxilofrine, deterenol, yohimbine, caffeine, and theophylline. Two more compounds were found which were tentatively identified as β‐methyl‐β‐phenylethylamines. This incident is only the next in a series of similar incidents involving dietary supplements with (undeclared) active substances that are either unsafe or have no known safety profile. Copyright © 2014 John Wiley & Sons, Ltd.     

Fluctuating high urinary phenylethylamine excretion rates in some bipolar affective disorder patients

Five women with primary major bipolar affective disorders had variable and at times very high urinary phenylethylamine (PEA) excretion rates. The clinical picture of these patients was characterized by periodic bizarre behaviors and short psychotic episodes. These patients were generally nonresponsive to the usual treatment modalities, and their symptoms were exacerbated by nonspecific monoamine oxidase inhibitors which further increased PEA excretion rates.     

Some factors affecting striatal 3-methoxytyramine concentrations in the mouse and rat

1. Apomorphine, a DA agonist, at a dose of 2 mg/kg, produced a rapid decline in 3-MT concentrations in the rat striatum; this is consistent with a reduction in the firing rate of nigrostriatal neurons.

2. The injection of a 12.5 mg/kg dose of phenylethylamine transiently increased 3-MT concentrations in the mouse striatum. A more profound increase was produced by this dose in the rat striatum.

3. Cocaine (5 mg/kg) produced a decrease in DOPAC concentrations in both species thus suggesting that the re-uptake of DA from the synaptic cleft in both species was very similar. Amfonelic acid, however, produced a different profile in each species.

4. The concentration of 3-MT is larger in the mouse striatum as a result of several possible mechanisms: the higher percentage of MAO isoenzyme B in the mouse brain (3-MT is a preferred substrate of MAO isoenzyme A) and/or due to differences in the clearance mechanisms for 3-MT produced extraneuronally — with the mouse having a less avid clearance system either for DA or for 3-MT.