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

Marvin K. Schulte, Robert J. Roon, David J. Chalmers, David C. Sunter, James F. Koerner

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)203-207
Number of pages5
JournalBrain Research
Volume649
Issue number1-2
DOIs
StatePublished - Jun 27 1994

Fingerprint

Quisqualic Acid
Pyramidal Cells
N-Methylaspartate
Organophosphonates
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Kainic Acid
Inhibitory Concentration 50
Perforant Pathway
Excitatory Amino Acids
Glutamate Receptors
Crystallization
Lysine
2-amino-6-phosphonohexanoic acid
Salts
Pharmacology
Neurons
2-amino-4-phosphonobutanoic acid receptor

Keywords

  • AP4
  • AP6
  • CA1 pyramidal neuron
  • EAA
  • Excitatory amino acid
  • Glutamate
  • Hippocampus
  • Quisqualate
  • Sensitization

Cite this

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. / Schulte, Marvin K.; Roon, Robert J.; Chalmers, David J.; Sunter, David C.; Koerner, James F.

In: Brain Research, Vol. 649, No. 1-2, 27.06.1994, p. 203-207.

Research output: Contribution to journalArticle

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abstract = "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.",
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T1 - 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

AU - Schulte, Marvin K.

AU - Roon, Robert J.

AU - Chalmers, David J.

AU - Sunter, David C.

AU - Koerner, James F.

PY - 1994/6/27

Y1 - 1994/6/27

N2 - 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.

AB - 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.

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KW - AP6

KW - CA1 pyramidal neuron

KW - EAA

KW - Excitatory amino acid

KW - Glutamate

KW - Hippocampus

KW - Quisqualate

KW - Sensitization

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U2 - 10.1016/0006-8993(94)91065-0

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