Alpha-keto acids, alpha-keto esters, diketopiperazines, 2,5-bis-alkoxy-3,6-dihydropyrazines, and morpholinediones as potential amino acid bioprecursors for delivery of an AMPA antagonist to the central nervous syste

The compound scL-2-hydroxy-3,5-dinitrophenylalanine (I) served as a prototypical triply ionized amino acid in this work.;Firstly, $alpha$-keto acid analogs of I were designed based on the rationale that they might serve as substrates for the same enzymes that are involved in the biosynthesis of neurotransmitter glutamate in some specific regions of the brain, and be converted to I only in those regions of the brain. None of the six different approaches (each based on literature precedents with similar compounds) to the synthesis of the desired $alpha$-keto acids and esters were fruitful: (1) benzyl Grignard addition to diethyl oxalate; (2) hydrolysis of an enamine obtained from a benzaldehyde and N,N-dimethylglycine; (3) hydrolysis of an enimide obtained from a benzaldehyde and N,N-diformylglycine ethyl ester; (4) stepwise hydrolysis of the above enimide by initial base hydrolysis of the ester to the acid; (5) hydrolysis of 2-benzyl-1,3-dithian-2-yl-carboxylic esters or acids; (6) enzymatic preparation with scD- or scL-amino acid oxidases. Except for method (2) each of these approaches failed only in the final step, and the mixtures ultimately obtained by the various methods (including enzymatic) contained at least some components in common. It seems highly likely that the $alpha$-keto ethyl ester is not stable enough for isolation, and probable that the $alpha$-keto acid is also not stable, perhaps in both cases due to the presence of the o-methoxy group.;A number of diketopiperazines were synthesized by cyclizing the appropriate linear dipeptide (LDP) esters. These represent a second type of bioprecursors, and are cyclic amino acid dimers in which at least one of the two residues is amino acid I. The requisite LDP esters were synthesized from suitably protected chiral amino acids, which were in turn obtained by using Aspergillus acylase to hydrolyze the N-acetylamino acids.;Dihydropyrazines (bislactim ethers, BLEs) comprised a third set of planned bioprecursors. These are imidate-masked DKPs, but BLEs are generally found to hydrolyze to esters in aqueous solution; since esterases are ubiquitous, ultimate conversion to the component amino acids is essentially assured, and may be more facile than for DKPs.;The fourth group of planned bioprecursors was a set of morpholinedione (MDO) derivatives, cyclic dimers of the amino acid I with $alpha$-hydroxy acids. The requisite N-haloacetyl amino acids and esters were synthesized, but attempted cyclization of these by several literature methods failed. A few dinitro-N-haloacetyl amino acids were cyclized with silver oxide in refluxing toluene, and were stable enough to be spectroscopically characterized, but not for satisfactory purification or storage. n-Octanol/water partition coefficient determinations and biotransformation studies in rat brain homogenates for the successfully synthesized bioprecursors are in progress, and microdialysis studies are planned. (Abstract shortened by UMI.).