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) sen sitizes neurons to depolarization by the alpha-amino-omega-phosphonate excitatory amino acid (EAA) analogues AP4, AP5 and AP6. These phospho nates 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 conjunction with the apparent preference of this site for L-isomers, suggested that the hitherto unavailable L-isomer of AP6 wou ld be a potent and specific agonist. We report the resolution of the D - and L-enantiomers of AP6 by fractional crystallization of the L-lysi ne salt of DL-AP6. We also report the pharmacological responses of kai nate/AMPA, NMDA, lateral perforant path L-AP4 receptors and the CA1 QU IS-sensitized site to D- and L-AP6, and compare these responses to the D- and L-isomers of AP3, AP4, PLP5 and AP7. The D-isomers of AP4, AP5 and AP6 were 5-, 3- and 14-fold less potent for the QUIS-sensitized s ite than their respective L-isomers. While L-AP4 and L-AP5 cross-react ed with NMDA and L-AP4 receptors, L-AP6 was found to be highly potent and specific for the QUIS-sensitized site (IC50 = 40 mu M). Its IC50 v alues 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 reve rsed by L-alpha-aminoadipate.