Conformationally-restricted amino acid analogues bearing a distal sulfonic acid show selective inhibition of system over the vesicular glutamate transporter

Etoga, Jean-Louis G.; Ahmed, S. Kaleem; Patel, Sarjubhai A.; Bridges, Richard J.; Thompson, Charles M.

doi:10.1016/j.bmcl.2009.10.020

Cited by 14 publications

(11 citation statements)

References 30 publications

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“…In contrast to ibotenate or QA, 4‐ S ‐CPG was essentially inactive as a S x c ‐ substrate when examined in the fluorometric exchange assay (Patel et al ., 2004). More recently, a 4‐ S ‐CPG derivative in which the distal carboxylate was replaced with a sulphonic acid (4‐ S ‐SPG) was also found to inhibit S x c ‐ (Etoga et al ., 2010). Unlike the analogous anionic substitution between l ‐Glu and l ‐homocysteate, 4‐ S ‐SPG was markedly less potent than 4‐ S ‐CPG, inhibiting uptake even less effectively than l ‐Cys 2 .…”

Section: Pharmacologymentioning

confidence: 99%

System x_c^‐ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS

Bridges

Natale

Patel

2011

British J Pharmacology

431

348

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System xc-is an amino acid antiporter that typically mediates the exchange of extracellular L-cystine and intracellular L-glutamate across the cellular plasma membrane. Studied in a variety of cell types, the import of L-cystine through this transporter is critical to glutathione production and oxidative protection. The exchange-mediated export of L-glutamate takes on added significance within the CNS, as it represents a non-vesicular route of release through which this excitatory neurotransmitter can participate in either neuronal signalling or excitotoxic pathology. When both the import of L-cystine and the export of L-glutamate are taken into consideration, system xc -has now been linked to a wide range of CNS functions, including oxidative protection, the operation of the blood-brain barrier, neurotransmitter release, synaptic organization, viral pathology, drug addiction, chemosensitivity and chemoresistance, and brain tumour growth. The ability to selectively manipulate system xc -, delineate its function, probe its structure and evaluate it as a therapeutic target is closely linked to understanding its pharmacology and the subsequent development of selective inhibitors and substrates. Towards that goal, this review will examine the current status of our understanding of system xc -pharmacology and the structure-activity relationships that have guided the development of an initial pharmacophore model, including the presence of lipophilic domains adjacent to the substrate binding site. A special emphasis is placed on the roles of system xc -within the CNS, as it is these actions that are among the most exciting as potential long-range therapeutic targets. Abbreviations4-S-CPG (S)-4-carboxyphenyglycine; 4-S-SPG, sulphonic acid phenylglycine; ACPA, amino-3-carboxy-5-methyl isoxazole propionic acid; trans-ACPD,1-aminocyclopentane-trans-1,3-dicarboxylic acid; ApcT, amino acid polyamine organo-cation transporter; ARE, antioxidant response element; ASC, alanine-serine-cysteine uptake systems; b-L-ODAP, L-b-N-oxalyl-L-a,b-diaminopropionate; BSO, buthionine sulphoximine; CPPG (R,S)-4-[4′-carboxyphenyl]-phenylglycine; dbcAMP, dibutyryl cyclic AMP; EAA, excitatory amino acid; EAAT, excitatory amino acid transporter; GSH, glutathione; HAT, heteromeric amino acid transporter family; iGluR, ionotropic glutamate receptor; KA, kainate; L-CysH, L-cysteine; L-Cys2, L-cystine; L-trans-2,4-PDC, L-trans-2,4-pyrrolidine dicarboxylate; mGluR, metabotropic glutamate receptor; NAC, N-acetyl-cysteine; NACPA, S-2-naphthyl-ethyl-ACPA; NEIH, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazonedinitrophenol; Nrf2, nuclear factor erythroid-2-related factor; QA, quisqualate; ROS, reactive oxygen species; SAR, structure-activity-relationship; SLC, solute carrier gene families, SSZ, sulphasalazine, ) is an amino acid antiporter that typically mediates the exchange of extracellular L-cystine (L-Cys2) and intracellular L-glutamate (L-Glu) across the cellular plasma membrane. Initial characterizations of this transporter most often focus...

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Section: Pharmacologymentioning

confidence: 99%

System x_c^‐ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS

Bridges

Natale

Patel

2011

British J Pharmacology

431

348

View full text Add to dashboard Cite

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“…6 Recently, Tsukamoto and co-workers explored the structure–activity relationship (SAR) of sulfasalazine and susalimod (SM) 7 analogs determined that the carboxylic acid is essential and that the diazo linker can be replaced with an alkyne, but that reduction to the alkene or alkyl tether lowered or abolished activity. Studies aimed at the development of 18 F-propyl-L-glutamate as an Sx c − PET imaging agent demonstrated that the S , S -isomer had superior binding affinity to the R , S -, 8 consistent with earlier observations that the transporter exhibits stereoselectivity of action.…”

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confidence: 99%

Microwave accelerated synthesis of isoxazole hydrazide inhibitors of the system xc- transporter: Initial homology model

Matti

Mirzaei

Rudolph

et al. 2013

Bioorganic & Medicinal Chemistry Letters

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Microwave accelerated reaction system (MARS) technology provided a good method to obtain selective and open isoxazole ligands that bind to and inhibit the Sxc− antiporter. The MARS provided numerous advantages, including: shorter time, better yield and higher purity of the product. Of the newly synthesized series of isoxazoles the salicyl hydrazide 6 exhibited the highest level of inhibitory activity in the transport assay. A homology model has been developed to summarize the SAR results to date, and provide a working hypothesis for future studies.

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“…Aryl- and heteroaryl sulfonic acid analogs, however, yielded only a few blockers with the desired selectivity. 16 Further examination of Sx c − specificity indicated that substituting a heterocyclic carboxylic acid isostere in place of the γ-carboxylate (ibotenate, quisqualate) yielded potent inhibitors. 17 Likewise, the inhibition of VGLUT may be accomplished with structures that incorporate a non-basic nitrogen (e.g., aniline, quinoline, etc.)…”

mentioning

confidence: 99%

“…This observation is consistent with work demonstrating that VGLUT interacts more strongly with glutamate analogs that contain non-basic amines. 16 …”

mentioning

confidence: 99%

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Use of the hydantoin isostere to produce inhibitors showing selectivity toward the vesicular glutamate transporter versus the obligate exchange transporter system

Ahmed¹,

Etoga²,

Patel³

et al. 2011

Bioorganic & Medicinal Chemistry Letters

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Evidence was acquired prior to suggest that the vesicular glutamate transporter (VGLUT) but not other glutamate transporters were inhibited by structures containing a weakly basic α-amino group. To test this hypothesis, a series of analogs using a hydantoin (pKa ~ 9.1) isostere were synthesized and analyzed as inhibitors of VGLUT and the obligate cystine-glutamate transporter (system xc−). Of the hydantoin analogs tested, a thiophene-5-carboxaldehyde analog 2l and a bis-hydantoin 4b were relatively strong inhibitors of VGLUT reducing uptake to less than 6% of control at 5 mM but few inhibited system xc− greater than 50% of control. The benzene-2,4-disulfonic acid analog 2b and p-diaminobenzene analog 2e were also good hydantoin-based inhibitors of VGLUT reducing uptake by 11% and 23% of control, respectively, but neither analog was effective as a system xc− inhibitor. In sum, a hydantoin isostere adds the requisite chemical properties needed to produce selective inhibitors of VGLUT.

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Conformationally-restricted amino acid analogues bearing a distal sulfonic acid show selective inhibition of system over the vesicular glutamate transporter

Cited by 14 publications

References 30 publications

System x_c^‐ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS

System x_c^‐ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS

Microwave accelerated synthesis of isoxazole hydrazide inhibitors of the system xc- transporter: Initial homology model

Use of the hydantoin isostere to produce inhibitors showing selectivity toward the vesicular glutamate transporter versus the obligate exchange transporter system

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Conformationally-restricted amino acid analogues bearing a distal sulfonic acid show selective inhibition of system over the vesicular glutamate transporter

Cited by 14 publications

References 30 publications

System xc‐ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS

System xc‐ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS

Microwave accelerated synthesis of isoxazole hydrazide inhibitors of the system xc- transporter: Initial homology model

Use of the hydantoin isostere to produce inhibitors showing selectivity toward the vesicular glutamate transporter versus the obligate exchange transporter system

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Resources

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System x_c^‐ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS

System x_c^‐ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS