Schulte M K, Roon R J, Chalmers D J, Sunter D C, Koerner J F
Department of Biochemistry, Medical School, University of Minnesota, Minneapolis 55455-0347.
Brain Res. 1994 Jun 27;649(1-2):203-7. doi: 10.1016/0006-8993(94)91065-0.
Brief exposure of rat hippocampal slices to quisqualic acid (QUIS) sensitizes neurons to depolarization by the alpha-amino-omega-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 conjunction 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 microM). 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-alpha-aminoadipate.
将大鼠海马切片短暂暴露于喹啉酸（QUIS）可使神经元对α-氨基-ω-膦酸兴奋性氨基酸（EAA）类似物AP4、AP5和AP6诱导的去极化敏感。这些膦酸与一个新的QUIS敏感位点相互作用。虽然L-AP4和D-AP5与其他EAA受体发生交叉反应，但已证明DL-AP6对QUIS敏感位点具有相对选择性。DL-AP6的这种特异性，加上该位点对L-异构体的明显偏好，表明迄今无法获得的AP6的L-异构体将是一种强效且特异的激动剂。我们报告了通过DL-AP6的L-赖氨酸盐分步结晶来拆分AP6的D-和L-对映体。我们还报告了海人藻酸/AMPA、NMDA、外侧穿通通路L-AP4受体以及CA1区QUIS敏感位点对D-和L-AP6的药理学反应，并将这些反应与AP3、AP4、AP5和AP7的D-和L-异构体的反应进行比较。AP4、AP5和AP6的D-异构体对QUIS敏感位点的效力分别比其各自的L-异构体低5倍、3倍和14倍。虽然L-AP4和L-AP5与NMDA和L-AP4受体发生交叉反应，但发现L-AP6对QUIS敏感位点具有高效力和特异性（IC50 = 40 μM）。其对海人藻酸/AMPA、NMDA和L-AP4受体的IC50值分别> 10 mM、3 mM和0.8 mM。与AP4和AP5一样，L-α-氨基己二酸可逆转对L-AP6的敏感性。
