Utilization of the resolved l-isomer of 2-amino-6-phosphonohexanoic acid (l-AP6) as a selective agonist for a quisqualate-sensitized site in hippocampal CA1 pyramidal neurons

Brief exposure of rat hippocampal slices to quisqualic acid (QUIS) sensitizes neurons to depolarization by the α-amino-ω-phosphonate excitatory amino acid (EAA) analogues AP4, AP5 and AP6. These phosphonates interact with a novel QUIS-sensitized site. Whereas l-AP4 and d-AP5 cross-react with other EAA receptors, dl-AP6 has been shown to be relatively selective for the QUIS-sensitized site. This specificity of dl-AP6, in conjuction with the apparent preference of this site for l-isomers, suggested that the hitherto unavailable l-isomer of AP6 would be a potent and specific agonist. We report the resolution of the d- and l-enantiomers of AP6 by fractional crystallization of the l-lysine salt of dl-AP6. We also report the pharmacological responses of kainate / AMPA, NMDA, lateral perforant path l-AP4 receptors and the CA1 QUIS-sensitized site to d- and l-AP6, and compare these responses to the d- and l-isomers of AP3, AP4, AP5 and AP7. The d-isomers of AP4, AP5 and AP6 were 5-, 3- and 14-fold less potent for the QUIS-sensitized site than their respective l-isomers. While l-AP4 and l-AP5 cross-reacted with NMDA and l-AP4 receptors, l-AP6 was found to be highly potent and specific for the QUIS-sensitized site (IC₅₀ = 40 μM). Its IC₅₀ values for kainate / AMPA, NMDA and l-AP4 receptors were > 10, 3 and 0.8 mM, respectively. As with AP4 and AP5, sensitization to l-AP6 was reversed by l-α-aminoadipate.