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  Development of New Photoswitchable Azobenzene Based γ-Aminobutyric Acid (GABA) Uptake Inhibitors with Distinctly Enhanced Potency upon Photoactivation

Lutz, T., Wein, T., Hoefner, G., Pabel, J., Eder, M., Dine, J., et al. (2018). Development of New Photoswitchable Azobenzene Based γ-Aminobutyric Acid (GABA) Uptake Inhibitors with Distinctly Enhanced Potency upon Photoactivation. JOURNAL OF MEDICINAL CHEMISTRY, 61(14), 6211-6235. doi:10.1021/acs.jmedchem.8b00629.

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 Creators:
Lutz, Toni1, Author
Wein, Thomas1, Author
Hoefner, Georg1, Author
Pabel, Joerg1, Author
Eder, Matthias1, Author
Dine, Julien2, Author           
Wanner, Klaus T.1, Author
Affiliations:
1external, ou_persistent22              
2Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035294              

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Free keywords: OPTICAL CONTROL; TRANSPORTERS; DERIVATIVES; GAT1; NEUROTRANSMITTER; BINDING; PHOTOPHARMACOLOGY; RECEPTORS; MECHANISM; CHANNELSPharmacology & Pharmacy;
 Abstract: A series of nipecotic acid derivatives with new azo benzene based photoswitchable N-substituents was synthesized and characterized in their (E)- and (Z)-form for their functional inhibitory activity at gamma aminobutyric acid transporters subtype 1 (GAT1), the most common gamma aminobutyric acid (GABA) transporter subtype in the central nervous system (CNS). This led to the identification of the first photoswitchable ligands exhibiting a moderate uptake inhibition of GABA in their (E)- but distinctive higher inhibitory potency in their (Z)-form resulting from photoirradiation. For the most efficient photoactivatable nipecotic acid derivative displaying an N-but-3-yn-1-yl linker with a terminal diphenyldiazene unit, an inhibitory potency of 4.65 +/- 0.05 (pIC(50)) was found for its (E)-form. which increased by almost two log units up to 6.38 +/- 0.04 when irradiated. The effect of this photoswitchable mGATl inhibitor has also been evaluated and confirmed in patch-clamp recordings in acute hippocampal slices from mice.

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Language(s): eng - English
 Dates: 2018
 Publication Status: Issued
 Pages: 25
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Degree: -

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Title: JOURNAL OF MEDICINAL CHEMISTRY
Source Genre: Journal
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Publ. Info: 1155 16TH ST, NW, WASHINGTON, DC 20036 USA : AMER CHEMICAL SOC
Pages: - Volume / Issue: 61 (14) Sequence Number: - Start / End Page: 6211 - 6235 Identifier: ISSN: 0022-2623