Design and synthesis of enantiomers of 3,5-dinitro-o-tyrosine

α- amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonists

Guoping Sun, Meri Slavica, Norman J. Uretsky, Lane J. Wallace, Gamal Shams, David M. Weinstein, John C. Miller, Duane Miller

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The R- and S-isomers of 3,5-dinitro-o-tyrosine (6a,b) have been synthesized though the use of chemoenzymatic synthesis and shown to bind differentially with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA, 3) receptors. The phenolic functional group of these o-tyrosine analogues was designed to act as a bioisostere of the γ-carboxyl group of glutamate. The S-isomer of 3,5-dinitro-o-tyrosine (6b) was 6.5 times more potent than the R-isomer (6a) in inhibiting [3H]AMPA binding with IC50 values of 13 ± 7 and 84 ± 26 μM, respectively. The phenolic group was important for binding affinity since the methoxy compound 7 was less potent than the phenolic compound 6 in inhibiting the binding of AMPA. The free amino group was also shown to be important since the N-acetyl analogue 15 and the N-t-BOC compounds 16 and 17 exhibited very low affinity for the AMPA receptors. AMPA receptor functional tests showed that the o-tyrosine analogues are antagonists and that S-isomer 6b (IC50 = 630 ± 140 μM) was more potent than the racemate 6 (IC50 = 730 ± 88 μM) while the R-isomer 6a was inactive up to 1 mM concentration, which is consistent with the S- isomer having higher binding affinity than the R-isomer.

Original languageEnglish (US)
Pages (from-to)1034-1041
Number of pages8
JournalJournal of Medicinal Chemistry
Volume41
Issue number7
DOIs
StatePublished - Mar 26 1998

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AMPA Receptors
Inhibitory Concentration 50
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Acids
Tyrosine
Glutamic Acid
3,5-dinitro-2-tyrosine

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Design and synthesis of enantiomers of 3,5-dinitro-o-tyrosine : α- amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonists. / Sun, Guoping; Slavica, Meri; Uretsky, Norman J.; Wallace, Lane J.; Shams, Gamal; Weinstein, David M.; Miller, John C.; Miller, Duane.

In: Journal of Medicinal Chemistry, Vol. 41, No. 7, 26.03.1998, p. 1034-1041.

Research output: Contribution to journalArticle

Sun, Guoping ; Slavica, Meri ; Uretsky, Norman J. ; Wallace, Lane J. ; Shams, Gamal ; Weinstein, David M. ; Miller, John C. ; Miller, Duane. / Design and synthesis of enantiomers of 3,5-dinitro-o-tyrosine : α- amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonists. In: Journal of Medicinal Chemistry. 1998 ; Vol. 41, No. 7. pp. 1034-1041.
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abstract = "The R- and S-isomers of 3,5-dinitro-o-tyrosine (6a,b) have been synthesized though the use of chemoenzymatic synthesis and shown to bind differentially with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA, 3) receptors. The phenolic functional group of these o-tyrosine analogues was designed to act as a bioisostere of the γ-carboxyl group of glutamate. The S-isomer of 3,5-dinitro-o-tyrosine (6b) was 6.5 times more potent than the R-isomer (6a) in inhibiting [3H]AMPA binding with IC50 values of 13 ± 7 and 84 ± 26 μM, respectively. The phenolic group was important for binding affinity since the methoxy compound 7 was less potent than the phenolic compound 6 in inhibiting the binding of AMPA. The free amino group was also shown to be important since the N-acetyl analogue 15 and the N-t-BOC compounds 16 and 17 exhibited very low affinity for the AMPA receptors. AMPA receptor functional tests showed that the o-tyrosine analogues are antagonists and that S-isomer 6b (IC50 = 630 ± 140 μM) was more potent than the racemate 6 (IC50 = 730 ± 88 μM) while the R-isomer 6a was inactive up to 1 mM concentration, which is consistent with the S- isomer having higher binding affinity than the R-isomer.",
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