Antagonist activity of methyl-substituted analogues of 2-amino-4-phosphonobutanoic acid in the hippocampal slice

Four monomethyl-substituted analogues of 2-amino-4-phosphonobutanoic acid (APB), an antagonist of excitatory pathways in the central nervous system, were prepared in order to investigate the steric requirements of the APB receptor. Methyl groups were incorporated at the amino, α-, β-, and γ-positions. The β- and γ-methyl-substituted analogues of APB were found to be moderately potent antagonists in excitatory synapses of the hippocampal perforant path, as judged by extracellular recording techniques, while the N- and α-methyl-substituted analogues had much lower potencies. All of these APB analogues had very low potencies in the Schaffer collateral pathway. The APB receptors in the perforant path displayed more tolerance of methyl-substitution at the β- and γ-positions of APB than at the amino or α-positions in this system.