Discovery of a subtype-selective of the human betaine/GABA transporter 1 (BGT-1) with a non-competitive pharmacological profile

TY - JOUR

T1 - Discovery of a subtype-selective of the human betaine/GABA transporter 1 (BGT-1) with a non-competitive pharmacological profile

AU - Kragholm, Bolette

AU - Kvist, Trine

AU - Madsen, Karsten Kirkegaard

AU - Jørgensen, Lars

AU - Vogensen, Stine Byskov

AU - Schousboe, Arne

AU - Clausen, Rasmus Prætorius

AU - Jensen, Anders A.

AU - Bräuner-Osborne, Hans

PY - 2013

Y1 - 2013

N2 - The γ-aminobutyric acid (GABA) transporters (GATs) are essential regulators of the activity in the GABAergic system through their continuous uptake of the neurotransmitter from the synaptic cleft and extrasynaptic space. Four GAT subtypes have been identified to date, each displaying different pharmacological properties and expression patterns. The present study focus on the human betaine/ GABA transporter 1 (BGT-1), which has recently emerged as a new target for treatment of epilepsy. However, the lack of selective inhibitors of this transporter has impaired the exploration of this potential considerably. With the objective of identifying novel compounds displaying selectivity for BGT-1, we performed a screening of a small compound library at cells expressing BGT-1 using a [3H]GABA uptake assay. The screening resulted in the identification of the compound N-(1-benzyl-4-piperidinyl)-2,4- dichlorobenzamide (BPDBA), a selective inhibitor of the human BGT-1 transporter with a noncompetitive profile exhibiting no significant inhibitory activity at the other three human GAT subtypes. The selectivity profile of the compound was subsequently confirmed at cells expressing the four mouse GAT subtypes. Thus, BPDBA constitutes a potential useful pharmacological tool compound for future explorations of the function of the BGT-1 subtype.

AB - The γ-aminobutyric acid (GABA) transporters (GATs) are essential regulators of the activity in the GABAergic system through their continuous uptake of the neurotransmitter from the synaptic cleft and extrasynaptic space. Four GAT subtypes have been identified to date, each displaying different pharmacological properties and expression patterns. The present study focus on the human betaine/ GABA transporter 1 (BGT-1), which has recently emerged as a new target for treatment of epilepsy. However, the lack of selective inhibitors of this transporter has impaired the exploration of this potential considerably. With the objective of identifying novel compounds displaying selectivity for BGT-1, we performed a screening of a small compound library at cells expressing BGT-1 using a [3H]GABA uptake assay. The screening resulted in the identification of the compound N-(1-benzyl-4-piperidinyl)-2,4- dichlorobenzamide (BPDBA), a selective inhibitor of the human BGT-1 transporter with a noncompetitive profile exhibiting no significant inhibitory activity at the other three human GAT subtypes. The selectivity profile of the compound was subsequently confirmed at cells expressing the four mouse GAT subtypes. Thus, BPDBA constitutes a potential useful pharmacological tool compound for future explorations of the function of the BGT-1 subtype.

U2 - 10.1016/j.bcp.2013.06.007

DO - 10.1016/j.bcp.2013.06.007

M3 - Journal article

SN - 0006-2952

VL - 86

SP - 521

EP - 528

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

ER -