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 γ-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.
Bibliographical noteFunding Information:
This research was supported by NIH Grant NS 17944 and a grant from the Minnesota Medical Foundation. R.K.F. is a recipient of NIH Training Grant 5T32-GM-7323. R.L.J. is a recipient of NIH Research Career Development Award HL00932.
- dianionic character
- extracellular recording
- glutamate analogues
- methyl substitution
- perforant path