5,5-Diaryl-2-amino-4-pentenoates as novel, potent, and selective glycine transporter type-2 reuptake inhibitors

Isaac, Methvin; Slassi, Abdelmalik; Silva, Kathleen Da; Arora, Jalaj; MacLean, Neil; Hung, Bill; McCallum, Kirk

doi:10.1016/s0960-894x(01)00253-0

Cited by 25 publications

(10 citation statements)

References 7 publications

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“…, 2007). Pentenoate derivatives were one of the earliest compound classes that provided antagonist discrimination for the GlyT2 transporter over that of GlyT1 (Isaac et al. , 2001).…”

Section: Blocking Glycine Transport Potentiates the Nmdar‐mediated Cumentioning

confidence: 99%

Glycine transport accounts for the differential role of glycine vs. d‐serine at NMDA receptor coagonist sites in the salamander retina

Stevens

Gustafson

Miller

2010

Eur J of Neuroscience

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In this study, we demonstrate that D-serine interacts with N-methyl-D-aspartate receptor (NMDAR) coagonist sites of retinal ganglion cells of the tiger salamander retina by showing that exogenous D-serine overcomes the competitive antagonism of 7-chlorokynurenic acid for this site. Additionally, we show that exogenous D-serine was more than 30 times as effective at potentiating NMDAR currents compared with glycine. We thus examined the importance of glycine transport through the application of selective antagonists of the GlyT1 (NFPS) and GlyT2 (ALX-5670) transport systems, while simultaneously evaluating the degree of occupancy of the NMDAR coagonist binding sites. Analysis was carried out with electrophysiological recordings from the inner retina, including whole-cell recordings from retinal ganglion cells and extracellular recordings of the proximal negative field potential. Blocking the GlyT2 transport system had no effect on the light-evoked NMDAR currents or on the sensitivity of these currents to exogenous D-serine. In contrast, when the GlyT1 system was blocked, the coagonist sites of NMDARs showed full occupancy. These findings clearly establish the importance of the GlyT1 transporter as an essential component for maintaining the coagonist sites of NMDARs in a non-saturated state. The normal, unsaturated state of the NMDAR coagonist binding sites allows modulation of the NMDAR currents, by release of either D-serine or glycine. These results are discussed in light of contemporary findings which favor D-serine over glycine as the major coagonist of the NMDARs found in ganglion cells of the tiger salamander retina.

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“…, 2007). Pentenoate derivatives were one of the earliest compound classes that provided antagonist discrimination for the GlyT2 transporter over that of GlyT1 (Isaac et al. , 2001).…”

Section: Blocking Glycine Transport Potentiates the Nmdar‐mediated Cumentioning

confidence: 99%

Glycine transport accounts for the differential role of glycine vs. d‐serine at NMDA receptor coagonist sites in the salamander retina

Stevens

Gustafson

Miller

2010

Eur J of Neuroscience

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“…The first GLYT2-selective inhibitor was the competitive inhibitor 4-benzyloxy-3,5-dimethoxy-N-[(1-dimethylaminocyclopentyl)methyl]benzamide (ORG 25543) (Caulfield et al, 2001), and other GLYT2-selective inhibitors belonging to different chemical classes have subsequently been developed (Isaac et al, 2001). GLYT1 and GLYT2 have several isoforms, thus increasing Gly transporter heterogeneity in the CNS (Aragón and López-Corcuera, 2003).…”

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confidence: 99%

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

et al. 2011

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“…Overall, fewer inhibitors are known for GlyT2. The competitive and selective inhibitor ORG 25543 was discovered first (Caulfield et al ., 2001) and followed by other classes of compounds (Isaac et al ., 2001).…”

Section: Pharmacology Of Slc6 Transportersmentioning

confidence: 99%

The solute carrier 6 family of transporters

Bröer

Gether

2012

British J Pharmacology

219

190

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The solute carrier 6 (SLC6) family of the human genome comprises transporters for neurotransmitters, amino acids, osmolytes and energy metabolites. Members of this family play critical roles in neurotransmission, cellular and whole body homeostasis. Malfunction or altered expression of these transporters is associated with a variety of diseases. Pharmacological inhibition of the neurotransmitter transporters in this family is an important strategy in the management of neurological and psychiatric disorders. This review provides an overview of the biochemical and pharmacological properties of the SLC6 family transporters. LINKED ARTICLESBJP published a themed section on Transporters in 2011. To view articles in this section visit

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5,5-Diaryl-2-amino-4-pentenoates as novel, potent, and selective glycine transporter type-2 reuptake inhibitors

Cited by 25 publications

References 7 publications

Glycine transport accounts for the differential role of glycine vs. d‐serine at NMDA receptor coagonist sites in the salamander retina

Glycine transport accounts for the differential role of glycine vs. d‐serine at NMDA receptor coagonist sites in the salamander retina

SLC6 Neurotransmitter Transporters: Structure, Function, and Regulation

The solute carrier 6 family of transporters

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