Neurotoxicology 2015 Dec 01;51:1-9. doi: 10.1016/j.neuro.2015.09.002.

Structure-dependent inhibition of the human α1β2γ2 GABAA receptor by piperazine derivatives: A novel mode of action.

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Piperazine derivatives are a class of psychoactive substances applied in prescription medicines like antidepressants as well as in drugs of abuse. They are known to increase brain levels of catecholamines, likely via reversal of reuptake transporters. However, other mechanisms could also contribute to increased neurotransmitter levels, e.g., reduced inhibitory inputs on catecholaminergic neurons. Inhibition of the main inhibitory input in the brain, the GABAergic system, by piperazine derivatives could contribute to increased neurotransmitter levels. Our previous studies support this by demonstrating that 1-(3-chlorophenyl)piperazine (3CPP/mCPP) is an antagonist of the human α1β2γ2 GABAA receptor (GABAA-R). We therefore investigated the effect of 12 additional piperazine derivatives on the function of the human α1β2γ2 GABAA-R expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique. Tested derivatives included benzylpiperazine (BZP), methylbenzylpiperazines (2/3MBP), phenylpiperazine (PP), methoxyphenylpiperazines (2/3/4MPP/MeOPP), chlorophenylpiperazines (2/4CPP) and fluorophenylpiperazines (4FPP/TFMPP). All derivatives concentration-dependently inhibited the GABA-evoked ion current. Chlorophenylpiperazines were the most potent GABAA-R antagonists; the IC20 value for 1-(2-chlorophenyl)piperazine (2CPP) was 46μM and 2CPP induced a maximum inhibition of ∼ 90% at 1mM. Derivatives can be ranked as follows from highest to lowest potency based on IC20 values: 2CPP>3MPP>4CPP>4MPP>2MBP>3CPP>PP>4FPP>2MPP>TFMPP>3MBP>BZP. This study demonstrates a novel mode of action of piperazine derivatives, i.e., antagonism of the GABAA-R. This mechanism can result in increased catecholamine levels that indirectly contribute to toxicity, e.g., adverse effects during overdoses. Therefore, this important mode of action is not only relevant for therapeutic psychiatric interventions, but could also proof valuable for therapeutic interventions in intoxications.

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Species referenced: Xenopus laevis
Genes referenced: gabarap zeb1