DESIGN AND SYNTHESIS OF ENANTIOMERS OF 3,5-DINITRO-O-TYROSINE - LPHA-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 synthes ized through the use of chemoenzymatic synthesis and shown to bind dif ferentially with the lpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoi c acid (AMPA, 3) receptors. The phenolic functional group of these o-t yrosine analogues was designed to act as a bioisostere of the gamma-ca rboxyl 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 [H-3]A MPA binding with IC50 values of 13 +/- 7 and 84 +/- 26 mu M, respectiv ely. The phenolic group was important for binding affinity since the m ethoxy compound 7 was less potent than the phenolic compound 6 in inhi biting 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 recept or functional tests showed that the o-tyrosine analogues are antagonis ts and that the S-isomer 6b (IC50 = 630 +/- 140 mu M) was more potent than the racemate 6 (IC50 = 730 +/- 88 mu M) while the R-isomer 6a was inactive up to 1 mM concentration, which is consistent with the S-iso mer having higher binding affinity than the R-isomer.