Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites

Sköld, Niklas; Nielsen, Birgitte; Olsen, Jacob Ingemar; Han, Ling; Olsen, Lars; Madsen, Ulf; Kristensen, Jesper L.; Pickering, Darryl S.; Johansen, Tommy N.

doi:10.1016/j.bmc.2014.07.045

Cited by 6 publications

(5 citation statements)

References 20 publications

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“…Although aryl iodides have been more commonly reported as coupling partners than aryl bromides in Negishi reactions with analogues of 6 , ,,,− we preferred to prepare the desired phenylalanine analogues using the latter due to commercial availability. To determine the best catalyst system for formation of 8 , we compared 1 H NMR spectra of crude Negishi product mixtures after aqueous workup for various catalyst combinations using bromobenzene as a model coupling partner.…”

Section: Resultsmentioning

confidence: 99%

“…On the basis of this SAR, it is impossible to say whether putative PC is Cell assay data was obtained at least in triplicate (wells). Amino acids were either purchased (50,93), synthesized according to Scheme 2 (92), or as previously published (98, 82 107 83,84 ). All compounds above are either single enantiomers of L configuration, or achiral (93), with the exception of the following compounds: 94-D (86% ee), 98 (78% ee), 98-D (80% ee), as determined by chiral HPLC analysis (Supporting Information).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…Amino acids were either purchased (50,93), synthesized according to Scheme 2 (92), or as previously published (98, 82 107 83,84 ). All compounds above are either single enantiomers of L configuration, or achiral (93), with the exception of the following compounds: 94-D (86% ee), 98 (78% ee), 98-D (80% ee), as determined by chiral HPLC analysis (Supporting Information). Compounds were tested at 200 μM for their ability to cause efflux (fmol/min) of [ 3 H]-gabapentin from preloaded HEK-hLAT1 cells.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)

et al. 2018

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The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)

et al. 2018

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“…The success rate of developing competitive agonists and antagonists that differentiate between the AMPA, KA, and NMDA receptors is relatively high. − Despite extensive efforts, however, the success rate for the development of subtype-selective orthosteric ligands within each of these iGluR families has been very low, especially true for the KA receptor. In fact, only GluK1 subtype-selective agonists and antagonists and the two GluK3-selective agonists CIP-AS ( 1a ) (GluK1/GluK3 = 110-fold; GluK2/GluK3 = 27-fold) , and LBG-20130 ( 1b ) (GluK1/GluK3 = ∼15-fold; GluK2/GluK3 = >15-fold) have been disclosed to this date …”

Section: Introductionmentioning

confidence: 99%

(S)-2-Mercaptohistidine: A First Selective Orthosteric GluK3 Antagonist

Poulie

Larsen

Leteneur

et al. 2022

ACS Chem. Neurosci.

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The development of tool compounds for the ionotropic glutamate receptors (iGluRs) remains an important research objective, as these are essential for the study and understanding of the roles of these receptors in health and disease. Herein, we report on the pharmacological characterization of (S)-2-hydroxyhistidine (2a) and (S)-2-mercaptohistidine (2b) as mediators of glutamatergic neurotransmission. While 2a displayed negligible binding affinity or activity at all glutamate receptors and transporters investigated, 2b displayed selectivity for homomeric GluK3 with binding affinities in the low micromolar range (K i = 6.42 ± 0.74 μM). The iGluR subtype selectivity ratio for 2b was calculated at ∼30-fold for GluK1/GluK3, GluA3/GluK3, and GluA4/GluK3 and >100-fold for GluK2/GluK3, GluA1/GluK3, and GluA2/GluK3. Unexpectedly, functional characterization of 2b revealed that the compound is an antagonist (K b = 7.6 μM) at homomeric GluK3 receptors while exhibiting only weak agonist activity at GluA2 (EC50 = 3.25 ± 0.55 mM). The functional properties of 2b were explored further in electrophysiological recordings of mouse hippocampal neurons.

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“…[14] In our search for new competitive AMPA receptor antagonists, we performed a rational design on the basis of known ligand binding modes within the GluA2 binding site. [15,[18][19][20][21] Structure-activity relationships have been developed for two alternate directions of structural modifications, including monocyclic and bicyclic phenylalanines, and within both series, the potent and selective antagonists of AMPA receptors and/or KA receptors have been identified (Figure 1a). One of them contains expanded versions of α-amino acid agonists-compounds built of an α-amino acid part linked through a heterocyclic ring system with a distal, negatively charged group.…”

Section: Introductionmentioning

confidence: 99%

Aryl‐ and heteroaryl‐substituted phenylalanines as AMPA receptor ligands

et al. 2017

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A series of racemic unnatural amino acids was rationally designed on the basis of recently published X-ray structures of the GluA2 LBD with bound phenylalanine-based antagonists. Twelve new diaryl- or aryl/heteroaryl-substituted phenylalanine derivatives were synthesized and evaluated in vitro in radioligand binding assays at native rat ionotropic glutamate receptors. The most interesting compound in this series, (RS)-2-amino-3-(3'-hydroxy-5-(1H-pyrazol-4-yl)-[1,1'-biphenyl]-3-yl)propanoic acid 7e, showed the binding affinity of 4.6 μm for native AMPA receptors and over fourfold lower affinity for kainic acid receptors. Furthermore, 7e was evaluated at recombinant homomeric rat GluA2 and GluA3 receptors. Recently reported X-ray structures 5CBR and 5CBS, representing two distinct antagonist binding modes, were used as templates for molecular docking of the synthesized series. Binding data supported with molecular modeling confirmed that aryl/heteroaryl-substituted phenylalanine analogues effectively bind to AMPA receptors with low micromolar affinity and high selectivity over native NMDA and kainate receptors. These properties make 7e a promising lead for the further development of new AMPA receptor ligands.

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Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites

Cited by 6 publications

References 20 publications

Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)

Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)

(S)-2-Mercaptohistidine: A First Selective Orthosteric GluK3 Antagonist

Aryl‐ and heteroaryl‐substituted phenylalanines as AMPA receptor ligands

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