Structure-function relationships for analogues of l-2-amino-4-phosphonobutanoic acid on the quisqualic acid-sensitive AP4 receptor of the rat hippocampus

Marvin K. Schulte, Edward R. Whittemore, James F. Koerner, Rodney L. Johnson

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Abstract

Hippocampal CA1 pyramidal cell neurons are sensitized to depolarization by l-2-amino-4-phosphonobutanoic acid (l-AP4) following exposure to l-quisqualic acid (QUIS). We have examined the interaction of 43 structural analogues of l-AP4 with both the 'induction' site and the QUIS-sensitive AP4 site in rat hippocampus. The synthesis of cis- and trans-4-phosphonoxyl-l-proline, 3-(RS)-amino-5-phosphonopentanoic acid and 2(RS)-amino-5-phenyl-4(RS)-phosphonopentanoic acid (γ-benzyl AP4) are described. None of the test compounds interact with the induction site; thus l-QUIS remains the only compound known to induce this effect. However, one compound (l-2-amino-3-(5-tetrazolyl) -propanoic acid (l-aspartate tetrazole) 'pre-blocked' and reversed the effects of QUIS. In addition, the potency of 16 analogues increased more than 4-fold following exposure of slices to l-QUIS. Among these, l-AP4, l-AP5, 2-amino-4-(methylphosphino) butanoic acid (AMPB), and E-1(RS)-amino-3(RS)-phosphonocyclopentanecarboxylic acid (E-cyclopentyl AP4) diplayed IC50 values of less than 0.100mM after QUIS. The results presented here suggest that the QUIS-sensitive AP4 site requires a spatial configuration of functional groups similar to that present in E-cyclopentyl AP4. The presence of a primary amino group and a phosphorus-containing group (either monoanionic or dianionic) appear to be required, however, a carboxyl group is not essential for interaction. The pharmacology of the QUIS-sensitive AP4 site suggest that it is distinct from other known binding sites for l-AP4 in the central nervous system (CNS).

Original languageEnglish (US)
Pages (from-to)291-298
Number of pages8
JournalBrain Research
Volume582
Issue number2
DOIs
StatePublished - Jun 12 1992

Bibliographical note

Funding Information:
Acknowledgements. The orgamc syntheses reported m this paper were supported by NIH Grant NS17944. We wash to acknowledge the advice and assistance of Stephen L. Crooks and Dawd Halsrud for these syntheses

Keywords

  • 2-Amino-4-phosphonobutanoic acid
  • CA1 pyramidal cell
  • Excitatory amino acid
  • Glutamate
  • Hippocampus
  • Sensitization

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