PMID- 26344803 OWN - NLM STAT- MEDLINE DCOM- 20161012 LR - 20181202 IS - 1872-9711 (Electronic) IS - 0161-813X (Linking) VI - 51 DP - 2015 Dec TI - Structure-dependent inhibition of the human alpha1beta2gamma2 GABAA receptor by piperazine derivatives: A novel mode of action. PG - 1-9 LID - S0161-813X(15)00131-X [pii] LID - 10.1016/j.neuro.2015.09.002 [doi] AB - 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 alpha1beta2gamma2 GABAA receptor (GABAA-R). We therefore investigated the effect of 12 additional piperazine derivatives on the function of the human alpha1beta2gamma2 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 46muM and 2CPP induced a maximum inhibition of approximately 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. CI - Copyright (c) 2015 Elsevier Inc. All rights reserved. FAU - Hondebrink, Laura AU - Hondebrink L AD - National Poisons Information Center (NVIC), University Medical Center Utrecht, P.O. Box 85500, NL-3508 GA Utrecht, The Netherlands. Electronic address: L.Hondebrink@umcutrecht.nl. FAU - Hermans, Elise J P AU - Hermans EJ AD - Neurotoxicology Research Group, Division Toxicology, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, NL-3508 Utrecht, The Netherlands. Electronic address: E.J.P.hermans@uu.nl. FAU - Schmeink, Stijn AU - Schmeink S AD - Neurotoxicology Research Group, Division Toxicology, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, NL-3508 Utrecht, The Netherlands. Electronic address: S.Schmeink@uu.nl. FAU - van Kleef, Regina G D M AU - van Kleef RG AD - Neurotoxicology Research Group, Division Toxicology, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, NL-3508 Utrecht, The Netherlands. Electronic address: G.vankleef@uu.nl. FAU - Meulenbelt, Jan AU - Meulenbelt J AD - National Poisons Information Center (NVIC), University Medical Center Utrecht, P.O. Box 85500, NL-3508 GA Utrecht, The Netherlands; Neurotoxicology Research Group, Division Toxicology, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, NL-3508 Utrecht, The Netherlands; Department of Intensive Care Medicine, University Medical Center Utrecht, P.O. Box 85500, NL-3508 GA Utrecht, The Netherlands. Electronic address: J.Meulenbelt-1@umcutrecht.nl. FAU - Westerink, Remco H S AU - Westerink RH AD - Neurotoxicology Research Group, Division Toxicology, Institute for Risk Assessment Sciences (IRAS), Faculty of Veterinary Medicine, Utrecht University, P.O. Box 80.177, NL-3508 Utrecht, The Netherlands. Electronic address: R.Westerink@uu.nl. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150904 PL - Netherlands TA - Neurotoxicology JT - Neurotoxicology JID - 7905589 RN - 0 (GABA-A Receptor Antagonists) RN - 0 (Piperazines) RN - 0 (Psychotropic Drugs) RN - 0 (Receptors, GABA-A) RN - 1RTM4PAL0V (Piperazine) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - Q3JTX2Q7TU (Diazepam) SB - IM MH - Animals MH - Diazepam/pharmacology MH - GABA-A Receptor Antagonists/*pharmacology MH - Humans MH - Piperazine MH - Piperazines/*chemistry/*pharmacology MH - Psychotropic Drugs/chemistry/*pharmacology MH - Receptors, GABA-A/*metabolism MH - Xenopus laevis MH - gamma-Aminobutyric Acid/pharmacology OTO - NOTNLM OT - 1(3-(Trifluoromethyl)phenyl)piperazine (TFMPP) OT - 1-Benzylpiperazine (BZP) OT - Antidepressants OT - Catecholamine OT - Drugs of abuse OT - Oocytes EDAT- 2015/09/08 06:00 MHDA- 2016/10/13 06:00 CRDT- 2015/09/08 06:00 PHST- 2013/10/25 00:00 [received] PHST- 2015/09/02 00:00 [revised] PHST- 2015/09/02 00:00 [accepted] PHST- 2015/09/08 06:00 [entrez] PHST- 2015/09/08 06:00 [pubmed] PHST- 2016/10/13 06:00 [medline] AID - S0161-813X(15)00131-X [pii] AID - 10.1016/j.neuro.2015.09.002 [doi] PST - ppublish SO - Neurotoxicology. 2015 Dec;51:1-9. doi: 10.1016/j.neuro.2015.09.002. Epub 2015 Sep 4.