LY300020, a conformationally constrained, o-tstrazole-containing analog of L-glutamic acid was prepared and has been shown to be a relatively potent, highly selective, systemicallyactive AMPA receptor agonist. The activity of LY300020 was shown to be highly stereoselective as its enantiomer, LY301900, was devoid of binding affinity at ionotropic excitatory amino acid receptors.L-Glutamic acid (Figure) is one of the principal endogenous ligands which indiscriminately activate excitatory amino acid (EAA) receptors (NMDA, AMPA, kainate, and metabotropic types) in the mammalian central nervous system. 1 Glutamate is a conformationally flexible molecule, possessingtwo key torsional angles (~1 and 22, Figure) which define the geometrical relationships between the a-amino acid and distal carboxylate functionalities. As part of our program aimed at understanding the effect of glutamic acid conformation on both potency at, and selectivity for, EAA receptors, we have prepared 2S,4R4-(1 H-tetr~ol-~yl)pyrrolidine-2-~~oxylic acid (L-bus-4-tetr~olylproline, 4a, LY300020) and 2R,4S-4-(1 H-tetr~ol-~yl)pyrrolidjne-2-~r~xyljc acid (D-WtfZS-4-tetraZO!yI-proline, 4b, LY301900) as conformationally restrained analogs of glutamate* possessing a tetrazole moiety as a bioisosterfc replacement for the o-carboxylate of the natural ligand.3