Design and Synthesis of Enantiomers of 3,5-Dinitro-o-tyrosine:  α-Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid (AMPA) Receptor Antagonists

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 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 the 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.