Antagonist activity of phosphorus-containing glutamate analogues in the perforant path

Two analogues of the amino acid L-2-amino-4-phosphonobutanoic acid (L-APB) were synthesized in order to test the hypothesis that the dianionic nature of the side chain is responsible for antagonism of excitatory synapses in the hippocampal perforant path. These compounds, DL-2-amino-4-(methylphosphino)-butanoic acid (DL-AMPB) and O-methylphosphonyl-L-serine (O-MPLS), possess singly-charged side chains and yet display antagonistic activity, illustrating that a dianionic charge on the side chain is not necessary for antagonism. Comparing structure-activity relationships for DL-AMPB, O-MPLS, L-APB, and O-phospho-L-serine (O-PLS), patterns of synaptic activity emerged which suggest that substitution of a methyl group for one of the phosphoryl hydroxyl groups lowers ligand potency in both medial and lateral pathways. Also, the nature of the atom at the gamma-position appears to alter the potency and degree of pathway selectivity of these ligands, a methylene unit imparting more potency and selectivity than an oxygen atom.