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Design, Synthesis and Pharmacological Characterization of Coumarin-Based Fluorescent Analogs of Excitatory Amino Acid Transporter Subtype 1 Selective Inhibitors, UCPH-101 and UCPH-102

Design, Synthesis and Pharmacological Characterization of Coumarin-Based Fluorescent Analogs of Excitatory Amino Acid Transporter Subtype 1 Selective Inhibitors, UCPH-101 and UCPH-102

Tri H V Huynh, Bjarke Abrahamsen, Karsten K Madsen, Alba Gonzalez-Franquesa, Anders A Jensen, Lennart Bunch

Bioorg Med Chem. 2012 Dec 1;20(23):6831-9.

PMID: 23072958

Abstract:

The excitatory amino acid transporters (EAATs) play a pivotal role in regulating the synaptic concentration of glutamate in the mammalian central nervous system. To date, five different subtypes have been identified, named EAAT15 in humans (and GLAST, GLT-1, EAAC1, EAAT4, and EAAT5, respectively, in rodents). Recently, we have published and presented a structure-activity relationship (SAR) study of a novel class of selective inhibitors of EAAT1 (and GLAST), with the analogs UCPH-101 (IC(50)=0.66μM) and UCPH-102 (IC(50)=0.43μM) being the most potent inhibitors in the series. In this paper, we present the design, synthesis and pharmacological evaluation of six coumarin-based fluorescent analogs of UCPH-101/102 as subtype-selective inhibitors at EAAT1. Analogs 1114 failed to inhibit EAAT1 function (IC(50) values >300μM), whereas analogs 15 and UCPH-102F inhibited EAAT1 with IC(50) values in the medium micromolar range (17μM and 14μM, respectively). Under physiological pH no fluorescence was observed for analog 15, while a bright blue fluorescence emission was observed for analog UCPH-102F. Regrettably, under confocal laser scanning microscopy selective visualization of expression of EAAT1 over EAAT3 was not possible due to nonspecific binding of UCPH-102F.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1229591563	UCPH-102		1229591-56-3	Price

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