N2-Acetylphenelzine : effects on rat brain GABA, alanine and biogenic amines

Abstract

The neurochemical properties of N2-acetylphenelzine were compared with those of phenelzine in a rat model. N2-Acetylphenelzine is a relatively potent inhibitor of monoamine oxidase-A and -B and causes increases in whole-brain levels of noradrenaline and 5-hydroxytryptamine, and decreases in homovanillic acid, 5-hydroxyindole-3-acetic acid, and 3,4-dihydroxyphenylacetic acetic after acute i.p. administration of the drug. Phenelzine is a more potent monoamine oxidase inhibitor than is N2-acetylphenelzine. The most marked difference in the profile was that N2-acetylphenelzine had no effect on whole brain levels of the amino acid neurotransmitters alanine and gamma-aminobutyric acid, whereas phenelzine caused dramatic increases. Acetylation of phenelzine at the N2 position presumably interferes with the inhibition of the transaminase enzymes for gamma-aminobutyric acid and alanine.

β‐phenylethylidenehydrazine, a novel inhibitor of GABA transaminase

“…Experiments in our laboratories have indicated that the GABA-elevating effect of PLZ is rather dramatic, occurring at reasonably low doses and remaining for lengthy periods after a single dose of PLZ McKenna et al, 1991;Parent et al, 2000]. Behavioral studies in the elevated plus maze test with PLZ and an analog (N 2 -acetylPLZ) which inhibits MAO but does not elevate brain GABA indicated that the antianxiety actions of PLZ are directly correlated to its ability to elevate brain GABA [Paslawski et al, 1996].…”

Phenelzine: An Old Drug That May Hold Clues to The Development of New Neuroprotective Agents

“…PLZ increases brain levels of the classical monoamine neurotransmitters (9)(10)(11)(12) and trace amines (phenylethylamine (PEA), tyramine and tryptamine) (13). However, it also inhibits GABA-transaminase (GABA-T) (10,14,15) and markedly increases brain levels of the inhibitory amino acid transmitter Á-aminobutyric acid (GABA) (10,(14)(15)(16)(17)(18)(19)(20)(21).…”

“…However, it also inhibits GABA-transaminase (GABA-T) (10,14,15) and markedly increases brain levels of the inhibitory amino acid transmitter Á-aminobutyric acid (GABA) (10,(14)(15)(16)(17)(18)(19)(20)(21). GABA-T requires pyridoxal phosphate (PLP) as a cofactor, and PLZ also inhibits a number of other PLP-dependent enzymes (22)(23)(24)(25).…”

Monoamine oxidase inhibition and neuroprotection by N1‐propargylphenelzine

“…N 2 -Acetylphenelzine, a derivative of the nonselective MAO-inhibiting antidepressant/antipanic drug phenelzine, has been shown to be a relatively potent non- MAO-A and MAO-B [McKenna et al, 1991] and to be neuroprotective [Urichuk et al, 1998]. N 2 -acetylphenelzine is also devoid of the brain γ-aminobutyric acid (GABA)-elevating effects seen with phenelzine [McKenna et al, 1991].…”

“…Additionally, such compounds would be expected to be devoid of GABAelevating activities, since this effect of phenelzine requires the presence of an unsubstituted hydrazine group [McKenna et al, 1991]. Furthermore, the possibility that subtle rearrangements in the chemical structures might provide compounds that could be selectively taken up and sequestered by certain cell types, thereby leading to cell-or tissue-specific effects, was considered.…”