Abstract

The excitatory amino acid transporters (EAATs) are transmembrane proteins responsible for the uptake of (S)-glutamate from the synaptic cleft. To date, five subtypes EAAT1-5 have been identified for which selective inhibitors have been discovered for EAAT1 and EAAT2. By screening of a commercially available compound library consisting of 4,000 compounds, N-acyl-N-phenylpiperazine analog (±)-exo-1 was identified to be a non-selective inhibitor at EAAT1-3 displaying IC50 values in the mid-micromolar range (10 μM, 40 μM and 30 μM at EAAT1, 2 and 3, respectively). Subsequently, we designed and synthesized a series of analogs to explore the structure-activity-relationship of this scaffold in the search for analogs characterized by increased inhibitory potency and/or EAAT subtype selectivity. Despite extensive efforts, all analogs of (±)-exo-1 proved to be either inactive or to have least 3-fold lower inhibitory potency than the lead, and furthermore none of the active analogs displayed selectivity for a particular subtype amongst the EAAT1-3. On the basis of our findings, we speculate that (±)-exo-1 binds to a recess (deepening) on the EAAT proteins than a well-defined pocket.

Highlights

  • In the central nervous system (CNS), the excitatory amino acid transporters (EAATs) are transmembrane proteins responsible for the uptake of (S)-glutamate (Glu) from the synaptic cleft

  • Five subtypes have been identified, named EAAT1–EAAT5 in humans and GLAST, GLT-1, EAAC1, EAAT4 and EAAT5, respectively, in rodents. (Bunch et al 2009) While EAAT5 is found exclusively in the retina, subtypes EAAT1–4 are expressed differentially within the CNS with respect to brain regions as well as at the cellular level: EAAT1 and EAAT2 are expressed primarily on astrocytes, but EAAT2 is found in neurons, astrocytes and oligodendrocytes. (Lauriat et al 2007) Subtype EAAT3 is

  • A conventional medicinal chemistry analysis of (±)-exo-1 suggests that the amide functionality, the aniline nitrogen, the phenyl ring and the trifluoromethyl group may play key roles in binding of this class of EAAT inhibitors

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Summary

Introduction

In the central nervous system (CNS), the excitatory amino acid transporters (EAATs) are transmembrane proteins responsible for the uptake of (S)-glutamate (Glu) from the synaptic cleft. General procedure a: synthesis of amides using O-benzotriazole-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) as coupling reagent To a suspension of the appropriate phenylpiperazine analog (0.33 mmol), the carboxylic acid (0.40 mmol) and TBTU (0.43 mmol) in dry DMF (4 mL) under an N2 atmosphere, was added DIPEA (1.32 mmol) and reaction mixture was stirred for 20 h at rt. General procedure B: synthesis of amides using acid chlorides To a suspension of 1-(3-(trifluoromethyl)phenyl)piperazine (4) (0.33 mmol) in dry dichloromethane (5 mL) at 0°C under a N2 atmosphere was added Et3N (0.91 mmol).

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