title: Design and synthesis of enantiomers of 3,5-dinitro-o-tyrosine: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonists.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee, Memphis 38163, USA.
authors.forename: G
authors.initials: G
authors.lastname: Sun
authors.forename: M
authors.initials: M
authors.lastname: Slavica
authors.forename: N J
authors.initials: NJ
authors.lastname: Uretsky
authors.forename: L J
authors.initials: LJ
authors.lastname: Wallace
authors.forename: G
authors.initials: G
authors.lastname: Shams
authors.forename: D M
authors.initials: DM
authors.lastname: Weinstein
authors.forename: J C
authors.initials: JC
authors.lastname: Miller
authors.forename: D D
authors.initials: DD
authors.lastname: Miller
mesh_terms: D000818:Animals; D015195:Drug Design; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C111685:3,5-dinitro-2-tyrosine; D011799:Quinazolines; D018091:Receptors, AMPA; D014443:Tyrosine