title: Structure-function relationships for analogues of L-2-amino-4-phosphonobutanoic acid on the quisqualic acid-sensitive AP4 receptor of the rat hippocampus.
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-phosphonoxy-L-proline, 3-(RS)-amino-5-phosphonopentanoic acid and 2(RS)-amino-5-phenyl-4(RS)-phosphonopentanoic acid (gamma-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) displayed IC50 values of less than 0.100 mM 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 suggests that it is distinct from other known binding sites for L-AP4 in the central nervous system (CNS).
authors.affiliation: Department of Biochemistry, Medical School, University of Minnesota, Minneapolis 55455.
authors.forename: M K
authors.initials: MK
authors.lastname: Schulte
authors.forename: E R
authors.initials: ER
authors.lastname: Whittemore
authors.forename: J F
authors.initials: JF
authors.lastname: Koerner
authors.forename: R L
authors.initials: RL
authors.lastname: Johnson
mesh_terms: D000613:Aminobutyrates / Q000494:pharmacology*; D000818:Animals; D006624:Hippocampus / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D015394:Molecular Structure; D016318:Quisqualic Acid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: C074680:2-amino-4-phosphonobutanoic acid receptor; D000613:Aminobutyrates; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter; D016318:Quisqualic Acid; C012729:2-amino-4-phosphonobutyric acid