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

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Glial Amino Acid Transporters

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 16))

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Abstract

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.

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Acknowledgment

SK and GE acknowledge funding provided by to the Austrian Science Fund (MolTag, grant # W1232).

Conflict of Interest

The author declares no conflicts of interest.

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Author notes

  1. Maria Damgaard and Anne Stæhr Haugaard contributed equally to this work.

Authors and Affiliations

  1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark

    Maria Damgaard, Anne Stæhr Haugaard, Anas Al-Khawaja, Maria E. K. Lie, Rasmus Prætorius Clausen & Bente Frølund

  2. Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090, Vienna, Austria

    Stefanie Kickinger & Gerhard F. Ecker

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  1. Maria Damgaard
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  2. Anne Stæhr Haugaard
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  1. Department of Toxicology, Cinvestav-IPN México City, México, Mexico

    Arturo Ortega

  2. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Arne Schousboe

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Damgaard, M. et al. (2017). Development of Non-GAT1-Selective Inhibitors: Challenges and Achievements. In: Ortega, A., Schousboe, A. (eds) Glial Amino Acid Transporters. Advances in Neurobiology, vol 16. Springer, Cham. https://doi.org/10.1007/978-3-319-55769-4_16

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