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Phenelzine is a monoamine oxidase (MAO) inhibitor used in treatment of depression and anxiety disorders. It also elevates brain levels of γ-aminobutyric acid (GABA) and inhibits primary amine oxidase (PrAO), an enzyme whose activity and/or expression has been reported to be increased in diabetes mellitus, Alzheimer's disease and cardiovascular disorders. Phenelzine is not only an inhibitor of, but also a substrate for, MAO and it has been suggested that an active metabolite, namely β-phenylethylidenehydrazine (PEH), is responsible for phenelzine's effects on amino acids. PEH is also a strong inhibitor of PrAO but has weak effects on MAO. PEH has a double bond and can thus exist as (E)- and (Z)-geometric isomers, but to date the two isomers have not been compared with regard to their neurochemical effects. We have investigated the effects of phenelzine, (E)- and (Z)-PEH on rat whole brain levels of amino acids, biogenic amine neurotransmitters and methylamine (an endogenous substrate of PrAO). Under the conditions used in the study, (E)- and (Z)-PEH appear to be equivalent in their neurochemical properties. Both PEH isomers and phenelzine produced marked increases in rat brain levels of GABA and alanine while decreasing brain levels of glutamine. Phenelzine increased brain levels of biogenic amine neurotransmitters (noradrenaline, dopamine and serotonin), whereas neither PEH isomer altered levels of these neurotransmitters to a considerable extent. All three drugs significantly increased rat brain levels of methylamine, with (E)- and (Z)-PEH causing a greater increase than phenelzine. These results are discussed in relation to the possible therapeutic applications of these drugs.

β-Phenylethylidenehydrazine (PEH) derivatives have been recognized as Gamma-aminobutyric acid aminotransferase (GABA-AT) inhibitors. In this research a group of newly synthesized of PEH analogs, possessing a variety of substituents (Me, OMe, Cl, and CF3) at the 2-, 3-, and 4-position of the phenyl ring, were subjected to docking study and quantitative structure activity relationship (QSAR) analysis. PEH analogs were built by HYPERCHEM program, and conformational studies were performed through semi-empirical method followed by PM3 method. QSAR descriptors were obtained from the EDRAGON and HYPERCHEM, and equations were derived from multilinear regression (MLR) method. The sums of the JGI2, H6m, and E2s were identified as the most significant descriptors. This simple equation can be used to estimate the GABA-AT inhibitory activity for new derivatives of this series of compounds. Docking study was performed by using AutoDock4 program on the all compounds. The obtained results show that the phenyl ring is inserted into the lipophilic pocket and that the NHNH2 moiety is situated in a mainly polar region of the enzyme. These computational studies can offer some useful references for understanding the action mechanism and performing the molecular design or modification of this series of GABA-AT inhibitors.

5 OZET: Fenelzin: Eski bir ilac, yeni noroprotektif ajanlar›n gelifltirilmesine ipuclar› tutabilir Panik bozukluk ve sosyal anksiyete bozukluu gibi anksiye- te bozukluklar›n›n tedavisinde kullan›lan monoamin oksi- daz (MAO) inhibitoru bir antidepresan olan fenelzinin geci- ci onbeyin iskemisi olan bir hayvan modelinde noroprotek- tif etkileri olduu gosterilmifltir. Fenelzinin MAO inhibisyo- nu etkisi yan› s›ra farmakolojik ve terapotik profiline ekle- nebilir cok say›da etkisi vard›r. Bu etkiler GABA transamina- z›n inhibisyonuyla beyin GABA duzeylerini artt›rmas›, glu- tamat›n ifllevsel durumu uzerine etkileri, reaktif aldehitlerin tutulumu, primer amin oksidaz inhibisyonu ve beyin kay- nakl› norotrofik faktor (BDNF) uzerindeki etkilerin inhibe edilmesidir. 2-Feniletilidenehidrazin, fenelzinin onemli bir metabolit olup GABA beyin duzeylerini artt›rd›¤› gosteril- mifltir ve gecici onbeyin iskemisi modelinde reaktif aldehit- lerin tutulumu ve noroprotektif etkileri keflfedilmifltir. Fe- nelzin ve feniletilidenehidrazin bu etkileri nedeniyle ozel- likle norodejenerasyon iceren psikiyatrik ve norolojik bo- zukluklar›n tedavisi icin gelecekte ilac tasar›m› yonunden goz onunde tutulmal›d›r. ABSTRACT: Phenelzine: An old drug that may hold clues to the development of new neuroprotective agents The monoamine oxidase (MAO)-inhibiting antidepressant phenelzine (PLZ) is also used in the treatment of anxiety disorders such as panic disorder and social anxiety disorder and has been shown to have neuroprotective actions in an animal model of transient forebrain ischemia. Phenelzine has multiple actions in addition to inhibition of MAO that may contribute to its pharmacological and therapeutic profile. These actions include inhibition of GABA transaminase and elevation of brain levels of GABA, effects on functional availability of glutamate, sequestration of reactive aldehydes, inhibition of primary amine oxidase and effects on brain-derived neurotrophic factor (BDNF). 2- Phenylethylidenehydrazine (PEH) has been identified as a major metabolite of PLZ and has also been shown to elevate brain levels of GABA, to sequester reactive aldehydes and to exert neuroprotective effects in a transient forebrain ischemia model. The actions of PLZ and PEH should be considered when designing future drugs for the treatment of psychiatric and neurologic disorders, particularly those involving neurodegeneration.

Changes in serotonin (5-hydroxytryptamine; 5-HT), noradrenaline (NA), and γ-aminobutyric acid (GABA) levels in the spinal cord are known to occur in response to nociceptive stimuli, yet little research has examined possible underlying sex differences in these changes and how they might affect nociception. We have used pharmacological approaches in a well established model of tonic nociception, the formalin test, to explore the effects of altering neurotransmitter levels on nociceptive responses in male and female C57BL/6 mice. The monoamine oxidase (MAO) inhibitor phenelzine (PLZ), its metabolite phenylethylidenehydrazine (PEH), and a derivative compound of PLZ, N 2 -acetylphenelzine (N 2 -AcPLZ), were used to increase endogenous levels of: GABA, 5-HT, and NA (PLZ); GABA alone (PEH); or 5-HT and NA only (N 2 -AcPLZ). Although both sexes had a reduction in second phase nociceptive behaviors with PEH pretreatment, the analgesic effect of PLZ was only observed in male mice. High performance liquid chromatography analysis revealed male mice had greater spinal cord increases in 5-HT and NA levels compared with female mice. Female mice, in contrast, had greater increases in GABA levels with pretreatments. With N 2 -AcPLZ pretreatment, only male mice had a reduction in second phase nociceptive behaviors despite similar increases in 5-HT and NA levels in both sexes. These findings suggest that male mice may utilize serotonergic and noradrenergic pathways more efficiently for the attenuation of nociceptive behavior and female mice are more dependent on alternate mechanisms. To our knowledge, these findings are the first on the antinociceptive properties of altering 5-HT, NA, and GABA levels with the MAO inhibitor PLZ and its derivatives in a model of tonic pain processing. They also reveal significant underlying sex differences associated with these treatments. Perspective The present study found that nociception in male and female mice may be regulated by different neurotransmitter systems. These results indicate that different pharmacological approaches may be needed to treat pain in both sexes.

β-Phenylethylidenehydrazine (PEH) has been demonstrated previously to be an inhibitor of γ-aminobutyric acid transaminase (GABA-T) and to cause a marked increase in rat brain levels of GABA, a major neurotransmitter. A group of PEH analogs, possessing a variety of substituents (Me, OMe, Cl, F, and CF3) at the 2-, 3-, and 4-positions of the phenyl ring, were synthesized for evaluation as inhibitors of GABA-T. The details of the synthesis and chemical characterization of the analogs are described. Preliminary in vitro screening for GABA-T inhibition showed that all the analogs possessed activity against this enzyme, although substitution of CF3 at the 2- and 4-positions caused reduced activity. One of the drugs, 4-fluoro-β-phenylethylidenehydrazine, was investigated further ex vivo, where it was shown to inhibit GABA-T, elevate brain levels of GABA, and decrease levels of glutamine, similar to the profile observed previously for PEH.

Phenelzine (PLZ) is a non-selective monoamine oxidase inhibitor (MAOI) commonly used to treat depression and panic disorder. As expected, PLZ increases brain levels of dopamine, norepinephrine, and serotonin. Interestingly, PLZ also elevates brain levels of γ-aminobutyric acid (GABA), and previous studies have suggested that these increases may also contribute to the anxiolytic effects of PLZ. Using in vivo microdialysis in conscious, freely moving rats, combined with high performance liquid chromatography, the present experiments determined that PLZ (15 or 30 mg/kg, free base weight) increases extracellular levels of GABA in the caudate-putamen and nucleus accumbens. The results also indicated that phenylethylidenehydrazine (PEH; 29.6 mg/kg, free base weight), a putative intermediate metabolite of PLZ that is not an MAOI, also significantly increases extracellular GABA levels in the caudate-putamen. These findings provide further evidence that GABA may play an important role in the actions of PLZ and suggest that PEH should be pursued further as a GABAergic drug in its own right.

Phenylethylidenehydrazine (PEH), a proposed metabolite of phenelzine (PLZ), was synthesized in our laboratories and administered to rats in a series of time- and dose–response studies. Phenelzine is a monoamine oxidase (MAO) inhibiting antidepressant/antipanic drug that also causes marked elevations of brain levels of the inhibitory neurotransmitter (γ-aminobutyric acid (GABA). Like PLZ, PEH inhibited GABA transaminase (GABA-T) and caused marked, long-lasting increases in rat brain levels of GABA. The addition of the double bond in PEH caused a marked decrease in its ability to inhibit MAO compared to PLZ. Given the ability of PEH to elevate GABA levels and its lack of significant effect on MAO, it may be a very effective and safe tool with which to study the role of GABA in anxiety disorders and may be a potentially useful compound to test against seizures, ischemia, mania, and stroke. Drug Dev. Res. 54:35–39, 2001. © 2001 Wiley-Liss, Inc.

Phenelzine, a non-selective irreversible inhibitor of monoamine oxidase (MAO), has been used in the treatment of depression and anxiety disorders for several decades. It is a unique inhibitor of MAO as it is also a substrate for MAO, with one of the metabolites being β-phenylethylidenehydrazine (PEH), and it also inhibits several transaminases (e.g. GABA transaminase) in the brain when administered i.p. to rats. Administration of either phenelzine or PEH to rats has been reported to produce dramatic increases in rat brain levels of GABA and alanine while reducing levels of glutamine; these effects are abolished for phenelzine, but not for PEH, when the animals are pre-treated with another MAO inhibitor, suggesting that they are mediated by the MAO-catalyzed formation of PEH from phenelzine. In the present report, we have found that phenelzine and E- and Z-geometric isomers of PEH significantly increased rat whole brain concentrations of L-tyrosine. In a time-response study, acute administration of phenelzine, E-PEH and Z-PEH (30 mg/kg i.p.) elevated rat whole brain L-tyrosine levels at 3 and 6h following injection, reaching approximately 265-305% of vehicle-treated controls at 3h. To determine whether the effect on L-tyrosine is MAO-dependent, animals were pre-treated with the non-selective MAO inhibitor tranylcypromine (1mg/kg i.p.) prior to administration of phenelzine, racemic PEH or vehicle controls. This pre-treatment reversed the effects of phenelzine, but not of PEH, on brain L-tyrosine levels, suggesting that the tyrosine-elevating property of phenelzine is largely the result of its active metabolite PEH. These results are discussed in relation to possible therapeutic applications of these drugs.

Phenylethylidenehydrazine (PEH), an analog of the monoamine oxidase inhibitor, β-phenylethylhydrazine (phenelzine), inhibits the γ-aminobutyric acid (GABA) catabolic enzyme GABA-transaminase and increases brain levels of GABA. GABA is the predominant fast inhibitory transmitter counteracting glutamatergic excitation, and increased neural GABA could influence a wide range of synaptic and circuit properties under both physiologic and pathophysiologic conditions. To examine the scope of these effects, we applied PEH (or vehicle) to rat hippocampal slices and measured basal glutamatergic transmission, synaptic plasticity, and epileptiform activity using extracellular field and whole cell patch clamp recordings. In vitro pre-treatment with PEH (100 μM) increased the GABA content of hippocampal slices by approximately 60% over vehicle-treated controls, but it had no effect on basal field excitatory postsynaptic potentials, tonic GABA currents, paired-pulse facilitation, or long-term potentiation. In contrast, pre-incubation with PEH caused a dose- and time-dependent reduction in epileptiform burst frequency induced by superfusion with Mg 2+ -free or high-K + artificial cerebrospinal fluid. Thus, the inhibitory effects of PEH are state-dependent: hyper-excitation during epileptiform bursting was reduced, whereas synaptic transmission and plasticity were unaffected.