Design and Synthesis of Enantiomers of 3,5-Dinitro-o-tyrosine: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid (AMPA) Receptor Antagonists
| Autor: | Guoping Sun, John C. Miller, G. Shams, Lane J. Wallace, Norman J. Uretsky, Meri Slavica, David M. Weinstein, Duane D. Miller |
|---|---|
| Rok vydání: | 1998 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry. 41:1034-1041 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm970276q |
| Popis: | The R- and S-isomers of 3,5-dinitro-o-tyrosine (6a,b) have been synthesized through the use of chemoenzymatic synthesis and shown to bind differentially with the alpha-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 gamma-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 microM, 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 the S-isomer 6b (IC50 = 630 +/- 140 microM) was more potent than the racemate 6 (IC50 = 730 +/- 88 microM) 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|