Development of Non-GAT1-Selective Inhibitors: Challenges and Achievements

TY - CHAP

T1 - Development of Non-GAT1-Selective Inhibitors

T2 - Challenges and Achievements

AU - Damgaard, Maria

AU - Haugaard, Anne Stæhr

AU - Kickinger, Stefanie

AU - Al-Khawaja, Anas

AU - Lie, Maria E K

AU - Ecker, Gerhard F

AU - Clausen, Rasmus Prætorius

AU - Frølund, Bente

PY - 2017

Y1 - 2017

N2 - γ-Aminobutyric acid (GABA) neurotransmission is terminated by the GABA transporters (GATs) via uptake of GABA into neurons and surrounding glial cells. Four different transporters have been identified: GAT1, GAT2, GAT3, and the betaine/GABA transporter 1 (BGT1). The GAT1 subtype is the most explored transporter due to its high abundance in the brain and the existence of selective and potent GAT1 inhibitors. Consequently, less is known about the role and therapeutic potential of the non-GAT1 subtypes. Emerging pharmacological evidence suggests that some of these transporters pose interesting targets in several brain disorders. Pharmacological non-GAT1-selective tool compounds are important to further investigate the involvement of GATs in different pathological conditions. Extensive medicinal chemistry efforts have been put into the development of subtype-selective inhibitors, but truly selective and potent inhibitors of non-GAT1 subtypes are still limited. This review covers the advances within the medicinal chemistry area and the structural basis for obtaining non-GAT1-selective inhibitors.

AB - γ-Aminobutyric acid (GABA) neurotransmission is terminated by the GABA transporters (GATs) via uptake of GABA into neurons and surrounding glial cells. Four different transporters have been identified: GAT1, GAT2, GAT3, and the betaine/GABA transporter 1 (BGT1). The GAT1 subtype is the most explored transporter due to its high abundance in the brain and the existence of selective and potent GAT1 inhibitors. Consequently, less is known about the role and therapeutic potential of the non-GAT1 subtypes. Emerging pharmacological evidence suggests that some of these transporters pose interesting targets in several brain disorders. Pharmacological non-GAT1-selective tool compounds are important to further investigate the involvement of GATs in different pathological conditions. Extensive medicinal chemistry efforts have been put into the development of subtype-selective inhibitors, but truly selective and potent inhibitors of non-GAT1 subtypes are still limited. This review covers the advances within the medicinal chemistry area and the structural basis for obtaining non-GAT1-selective inhibitors.

KW - Journal Article

U2 - 10.1007/978-3-319-55769-4_16

DO - 10.1007/978-3-319-55769-4_16

M3 - Book chapter

C2 - 28828618

VL - 16

T3 - Advances in Neurobiology

SP - 315

EP - 332

BT - Advances in Neurobiology

PB - Springer

ER -