Table 1

Comparison of potency of EAA analogs for inhibition of GLT-1-mediated transport activity

CompoundIC50 (μM) or % Inhibition
LM-GLT1–8MCB-GLT1–6Cortical synaptosomesCerebellar synaptosomes
Part A: Compounds with <10-fold selectivity comparing cortical and cerebellar tissue
   1.  l-cysteate (S)24.7  ± 1614.7  ± 2.12.01-a 1.51-a 
  l-anti-endo-3,4-methanopyrrolidine  dicarboxylate (T)12.8  ± 1.032.5  ± 14.6Not TestedNot Tested
   2.  l-trans-PDC (T)16.2  ± 5.810.2  ± 0.82.31-a 1.61-a
   3.  d-aspartate (S)29.8  ± 2.211.9  ± 0.93.11-a 1.71-a
   4.  l-aspartate (S)25.8  ± 2.918.3  ± 4.73.51-a 1.51-a
   5.  dl-threo-β-hydroxyaspartate (C)20.7  ± 6.016.7  ± 1.42.31-b 3.41-b
   6.  l-2-amino-3-phosphonopropionate (T)1432  ± 3472341  ± 3591101-a 391-a
   7.  n-methyl-d-aspartate (T)17  ± 4% at 1 mM27  ± 8% at 1 mM4301-a 3301-a
Part B: Compounds with >10-fold selectivity comparing cortical and cerebellar tissue
   8.  (RS)-α-amino-3-hydroxy-5-methylisoxazole-4-propionate (T)324  ± 32378  ± 4253% at 1 mM1-a 22% at 1 mM1-a
   9.  β-N-oxalyl-l-α,β-diaminopropionate (T)14  ± 5% at 1 mM8  ± 3% at 1 mM20% at 1 mM1-a 2801-a
  10.  dihydrokainate (G)50.0  ± 20.031.6  ± 6.51201-b 16% at 3 mM1-b
(2S, 1′S, 2′S)-2-(carboxycyclopropyl)19  ± 4% at 1 mM−2  ± 5% at 1 mM16% at 1 mM1-a 1401-a
  11.  glycine (T) α-methyl-dl-glutamate (S)3  ± 3% at 1 mM−15  ± 14% at 1 mM14% at 1 mM1-a  911-a
  12.  l-α-aminoadipate (S)3315  ± 1042434  ± 4868001-b  401-b
Part C: Compounds with data for inhibition that are best fit to two sites in either cortical and cerebellar tissue
  13.  kainate (S)53.4  ± 3.470.5  ± 19High  72 (71%)1-a High  53 (83%)1-a
Low  3,500 (21%)Insensitive (23%)
  14.  l-homocysteate (S)11  ± 10% at 1 mM5  ± 4% at 1 mMHigh  51 (25%)1-a 551-a
Low  1600 (76%)
  15.  quisqualate (T)1565  ± 3921970  ± 216High  0.22 (8%)1-a High  0.67 (10%)1-a
Low  755 (92%)Low  108 (88%)

  • The Na+-dependent transport ofl-[3H]-glutamate (0.5 μM) was measured in the absence and presence of increasing concentrations of inhibitor. All data are mean ± S.E.M. values of at least three independent observations. IC50 values were obtained by fitting the data to one site using GraphPad Prism software. The numbers that precede the name of each compound were used to identify individual points on the graphs correlating the potencies of each compound for inhibition of GLT-1-mediated transport and inhibition of transport activity in cortical or cerebellar synaptosomes (Fig. 5).

  • The sources for the compounds used in this study are abbreviated in parentheses after the name of the compound: C, Calbiochem; G, Genosis; T, Tocris; S, Sigma.

  • ↵1-a Data from Robinson et al., 1993.

  • ↵1-b Data from Robinson et al., 1991.