Exploration of N-Phosphonoalkyl-, N-Phosphonoalkenyl-, and N-(Phosphonoalkyl)phenyl-Spaced α-Amino Acids as Competitive N-Methyl-D-aspartic Acid Antagonists

Article abstract of DOI:10.1021/jm00086a005

A series of N-substituted α-amino acids containing terminal phosphonic acid groups has been synthesized as potential N-methyl-D-aspartate (NMDA) receptor antagonists.NMDA receptor affinity was determined by displacement of a known ligand (<3H>CPP) from crude rat brain synaptic membranes; an antagonists action was demonstrated by the inhibition of glutamate-induced accumulation of (45Ca²⁺> in cultured rat cortical neurons.Receptor affinity was significantly correlated with antagonist activity (Figure 1).Moderate affinity (IC50 = 1-2 μM) was retained for analogues (31 and 32, Table I; and 59 and 66, Table II) with reduced flexibility in their phosphonate side chains and is consistent with entropy playing a role in determining receptor affinity.Modeling studies suggest a folded conformation that brings the distal phosphonic acid group into close proximity with the α-carboxylate is required for binding.Each of the active analogues possess entropy-limiting features (double bonds, phenyl rings) in their side chains that allows the superposition of their key NH2, α-COOH, and distal PO3H2 groups with those of known competitive antagonists.Affinity decreased for analogues with α-carbon substitution, presumably because the α-substituent inhibits the folding of these structures into a bioactive conformation and occupies receptor-excluded volume.A complete description of the NMDA antagonist pharmacophore model is provided in a companion paper.