Structure activity relationship of selective GABA uptake inhibitors

Stine Byskov Vogensen; Lars Jørgensen; Karsten K Madsen; Andreas Jurik; Nrupa Borkar; Emiliano Rosatelli; Birgitte Nielsen; Gerhard F Ecker; Arne Schousboe; Rasmus Prætorius Clausen

doi:10.1016/j.bmc.2015.03.060

Structure activity relationship of selective GABA uptake inhibitors

Stine Byskov Vogensen, Lars Jørgensen, Karsten K Madsen, Andreas Jurik, Nrupa Borkar, Emiliano Rosatelli, Birgitte Nielsen, Gerhard F Ecker, Arne Schousboe, Rasmus Prætorius Clausen

24 Citationer (Scopus)

Abstract

A series of β-amino acids with lipophilic diaromatic side chain was synthesized and characterized pharmacologically on mouse γ-amino butyric acid (GABA) transporter subtypes mGAT1-4 in order to investigate structure activity relationships (SAR) for mGAT2 (corresponding to hBGT-1). Variation in the lipophilic diaromatic side chain was probed to understand the role of the side chain for activity. This yielded several selective compounds of which the best (1R,2S)-5a was more than 10 fold selective towards other subtypes, although potency was moderate. A docking study was performed to investigate possible binding modes of the compounds in mGAT2 suggesting a binding mode similar to that proposed for Tiagabine in hGAT1. Specific interactions between the transporter and the amino acid part of the ligands may account for a reverted preference towards mGAT2 over mGAT1.

Originalsprog	Engelsk
Tidsskrift	Bioorganic & Medicinal Chemistry
Vol/bind	23
Udgave nummer	10
Sider (fra-til)	2480-2488
Antal sider	9
ISSN	0968-0896
DOI	https://doi.org/10.1016/j.bmc.2015.03.060
Status	Udgivet - 15 maj 2015

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10.1016/j.bmc.2015.03.060

Citationsformater

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title = "Structure activity relationship of selective GABA uptake inhibitors",

abstract = "A series of β-amino acids with lipophilic diaromatic side chain was synthesized and characterized pharmacologically on mouse γ-amino butyric acid (GABA) transporter subtypes mGAT1-4 in order to investigate structure activity relationships (SAR) for mGAT2 (corresponding to hBGT-1). Variation in the lipophilic diaromatic side chain was probed to understand the role of the side chain for activity. This yielded several selective compounds of which the best (1R,2S)-5a was more than 10 fold selective towards other subtypes, although potency was moderate. A docking study was performed to investigate possible binding modes of the compounds in mGAT2 suggesting a binding mode similar to that proposed for Tiagabine in hGAT1. Specific interactions between the transporter and the amino acid part of the ligands may account for a reverted preference towards mGAT2 over mGAT1.",

author = "Vogensen, {Stine Byskov} and Lars J{\o}rgensen and Madsen, {Karsten K} and Andreas Jurik and Nrupa Borkar and Emiliano Rosatelli and Birgitte Nielsen and Ecker, {Gerhard F} and Arne Schousboe and Clausen, {Rasmus Pr{\ae}torius}",

year = "2015",

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doi = "10.1016/j.bmc.2015.03.060",

language = "English",

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T1 - Structure activity relationship of selective GABA uptake inhibitors

AU - Vogensen, Stine Byskov

AU - Jørgensen, Lars

AU - Madsen, Karsten K

AU - Jurik, Andreas

AU - Borkar, Nrupa

AU - Rosatelli, Emiliano

AU - Nielsen, Birgitte

AU - Ecker, Gerhard F

AU - Schousboe, Arne

AU - Clausen, Rasmus Prætorius

PY - 2015/5/15

Y1 - 2015/5/15

N2 - A series of β-amino acids with lipophilic diaromatic side chain was synthesized and characterized pharmacologically on mouse γ-amino butyric acid (GABA) transporter subtypes mGAT1-4 in order to investigate structure activity relationships (SAR) for mGAT2 (corresponding to hBGT-1). Variation in the lipophilic diaromatic side chain was probed to understand the role of the side chain for activity. This yielded several selective compounds of which the best (1R,2S)-5a was more than 10 fold selective towards other subtypes, although potency was moderate. A docking study was performed to investigate possible binding modes of the compounds in mGAT2 suggesting a binding mode similar to that proposed for Tiagabine in hGAT1. Specific interactions between the transporter and the amino acid part of the ligands may account for a reverted preference towards mGAT2 over mGAT1.

AB - A series of β-amino acids with lipophilic diaromatic side chain was synthesized and characterized pharmacologically on mouse γ-amino butyric acid (GABA) transporter subtypes mGAT1-4 in order to investigate structure activity relationships (SAR) for mGAT2 (corresponding to hBGT-1). Variation in the lipophilic diaromatic side chain was probed to understand the role of the side chain for activity. This yielded several selective compounds of which the best (1R,2S)-5a was more than 10 fold selective towards other subtypes, although potency was moderate. A docking study was performed to investigate possible binding modes of the compounds in mGAT2 suggesting a binding mode similar to that proposed for Tiagabine in hGAT1. Specific interactions between the transporter and the amino acid part of the ligands may account for a reverted preference towards mGAT2 over mGAT1.

U2 - 10.1016/j.bmc.2015.03.060

DO - 10.1016/j.bmc.2015.03.060

M3 - Journal article

C2 - 25882526

SN - 0968-0896

VL - 23

SP - 2480

EP - 2488

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 10

ER -

Structure activity relationship of selective GABA uptake inhibitors

Abstract

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