Formation of β-phenylethylamine from the antidepressant, β-phenylethylhydrazine
Abstract
To determine whether the monoamine oxidase inhibitor phenelzine was metabolized in vivo to produce β-phenylethylamine (PE) and p-hydroxy-β-phenylethylamine [p-tyramine (pTA)], a deuterated analogue, α,α,,β,β-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 μg d4-PE. These results clearly indicate that the antidepressant phenelzine was metabolized in vivo to produce the trace amine PE.
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Cited by (28)
Comparison of neurochemical effects of the monoamine oxidase inhibitors phenelzine, moclobemide and brofaromine in the rat after short- and long-term administration
2000, Journal of Affective DisordersBackground: Chronic administration of several irreversible monoamine oxidase (MAO) inhibitors induces a down-regulation of tryptamine and 5-hydroxytryptamine2 receptors in rat brain, but there is a paucity of information available on the effects of reversible MAO-A inhibitors on these receptors. Methods: Acute and chronic experiments were conducted in rats and the effects of the irreversible monoamine oxidase inhibitor, phenelzine and the reversible MAO type-A inhibitors, moclobemide and brofaromine, on tryptamine and 5-hydroxytryptamine2 receptors were analysed using radioligand binding techniques. In addition, activities of MAO-A and -B were determined radiochemically and brain and/or urine levels of tryptamine, 5-hydroxytryptamine, 3-methoxy-4-hydroxyphenylglycol (MHPG), β-phenylethylamine, brofaromine and moclobemide were determined by chromatographic procedures. Results: After 30 days of administration, moclobemide and brofaromine selectively inhibited brain MAO-A activity and phenelzine inhibited MAO-A and -B to equal extents. All three drugs caused a significant down-regulation of tryptamine receptors, whereas only phenelzine significantly down-regulated 5-hydroxytryptamine2 receptors. In a comparison of phenelzine and brofaromine, both caused marked elevations of urinary tryptamine and decreases of urinary MHPG levels, while only phenelzine increased β-phenylethylamine levels. After 14 days of administration, phenelzine, but not moclobemide or brofaromine, significantly increased levels of tryptamine in brain; all three drugs significantly increased 5-HT levels. Limitations: 24-h urine samples were not collected for moclobemide-treated animals and brain levels of tryptamine were not measured after 30-day administration. Conclusions: These studies revealed marked neurochemical differences among phenelzine, moclobemide and brofaromine which could contribute to their actions in the clinical setting.
Effects of the MAO inhibitor phenelzine on glutamine and GABA concentrations in rat brain
1995, Progress in Brain ResearchPhenelzine (PLZ), a frequently prescribed monoamine oxidase (MA01 inhibitor, is used as an antidepressant/antipanic drug and has been shown to cause marked increases in the rat brain levels of the amino acids—namely, y-aminobutyric acid (GABA) and alanine. It investigates the effects of PLZ on the rat brain levels of glutamine (GLN). At 1, 3, or 6 h after the injection of PLZ, rats were killed and the brains removed. Analyses (using HPLC with fluorescence detection of OPT derivatives) of the whole brain or hypothalamus revealed a decrease in brain levels of GLN and an increase in GABA levels at 3 and 6 h after PLZ injection. The effects of PLZ on GLN and GABA were blocked by a prior treatment of the rats with tranylcypromine, a MAO inhibitor that had been shown previously to have no direct effect itself on GABA levels in the rat brain. Because PLZ is known to be a substrate (as well as an inhibitor) of MAO, the studies with tranylcypromine pretreatment suggest that the effects on GLN and GABA are caused, at least in part, by a metabolite of PLZ.
Effects of monoamine oxidase inhibitors on the acid metabolites of some trace amines and of dopamine in the rat striatum
1993, Biochemical PharmacologyThe 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 α-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 its removal via transport or further metabolism regulates its concentration.
Conjugation of phenylacetic acid and m- and p-hydroxyphenylacetic acids in the rat striatum
1993, Life SciencesTwo factors that might regulate the levels of the trace acids, phenylacetic acid (PAA), m-hydroxyphenylacetic acid (mHPAA) and p-hydroxyphenylacetic acid (pHPAA) in the rat striatum were investigated: first, formation of conjugates of these acids and second, transport out of the brain by a probenecid-sensitive system. The presence of conjugates of these acids was investigated by subjecting homogenates of rat striatum to hydrolysis. The concentrations of PAA were increased ten-fold by hydrolysis, pHPAA increased two-fold, and mHPAA was unaffected. These findings coupled with the failure of pargyline to decrease free or total PAA levels suggest that conjugation of PAA is an important factor regulating free PAA levels. The transport inhibitor, probenecid, increased the concentrations of free mHPAA, free pHPAA and the total concentrations of all three acids indicating that all three trace acids can be removed from the rat brain by a transport system.
Induction of functional down‐regulation of β‐adrenoceptors in rats by 2‐phenylethylamine
1993, Journal of Pharmaceutical SciencesThe effects of chronic administration of antidepressant drugs and 2-phenylethylamine on β-adrenoceptor function were assessed. Monoamine oxidase inhibitors [phenelzine sulfate, 5 or 10 mg kg−1 per day, and (−)-deprenyl HCI, 1 mg kg−1 per day] and 2-phenylethylamine HCI (10 mg kg−1 per day) were administered to male Sprague-Dawley rats via Alzet osmotic minipumps. On days 21 and 22, the motor-suppressant actions of the β-adrenoceptor agonist salbutamol hemisulfate (3 mg kg−1 intraperitoneally after 15 min) were assessed as a measure of β-adrenoceptor sensitivity. On day 28, the animals were killed, and their brains were used for the measurement of monoamine oxidase activity and concentrations of 2-phenylethylamine, an endogenous amine and a metabolite of phenelzine. Phenelzine sulfate at 10 mg kg−1 per day (but not 5 mg kg−1 per day) and the combination of (−)-deprenyl and 2-phenylethylamine resulted in a decrease in the response to salbutamol. These treatments also resulted in substantial increases in brain 2-phenylethylamine concentrations. The phenelzine treatments each resulted in an equivalent inhibition of brain monoamine oxidase activity. These results support the proposal that 2-phenylethylamine may, at least in part, mediate the effects of phenelzine on β-adrenoceptor function.
β-adrenoceptors and antidepressants: Possible 2-phenylethylamine mediation of chronic phenelzine effects
1991, Biological PsychiatryEffects of chronic administration of antidepressant drugs on β-adrenoceptor function were assessed. Tricyclics (imipramine 30 mg/kg/day, desipramine 5 and 10 mg/kg/day) and monoamine oxidase inhibitors [(±)-tranylcypromine 1 mg/kg/day, phenelzine 5 and 10 mg/kg/day] were administered to Male Sprague-Dawley rats (n = 8), via Alzet 2ML2 osmotic minipumps for 28 days. Pumps were implanted subcutaneously in the interscapular region and replaced after 14 days. On days 21 and 22 motor-suppressant actions of the β-adrenoceptor agonist salbutamol (3 mg/kg intraperitoneally [IP]) were assessed as a measure of β-adrenergic receptor sensitivity. On day 28 the animals were killed and their brains used for measurement of drug levels and monoamine oxidase activity. Liver tissue was used to measure the trace amine 2-phenylethylamine. Each drug induced a decrease in the response to salbutamol. With phenelzine the decreased response to salbutamol was not observed at the lower dose. Differences in monoamine oxidase inhibition following phenelzine did not correspond to differential effects on functional β-adrenergic sensitivity. Levels of 2-phenylethylamine, an endogenous amine that is also a metabolite of phenelzine, were significantly higher in the 10-mg/kg/day phenelzine group. These data suggest that 2-phenylethylamine may be one mediator of the chronic actions of phenelzine on β-adrenoceptors.