STRUCTURE ACTIVITY RELATIONS OF N-METHYL-D-ASPARTATE RECEPTOR LIGANDS AS STUDIED BY THEIR INHIBITION OF [H-3]D-2-AMINO-5-PHOSPHONOPENTANOIC ACID BINDING IN RAT-BRAIN MEMBRANES

Structure/activity relations of agonists and antagonists for the N-methyl-D-aspartate receptor have been investigated by measuring the ability of a large range of substances to inhibit binding of [3H]2-amino-5-phosphonopentanoate to rat brain membranes. A major difference between optimum structures for agoist and antagonist activity lay in the differential effectiveness of sulphonic and phosphonic acid groups as the .omega.-acidic terminal in these two types of compound. The sulphonic acid moiety was an effective .omega.-acidic terminal in short chain agonists, but not in longer chain antagonists, while the phosphonic acid group was the most effective .omega.-acidic terminal in longer chain antagonists, but was only very weakly active in short chain agonists. It is proposed that the binding site of the .omega.-acidic terminal of antagonists is different from that for the .omega.-acidic group of agonists. Other structural features conductive to effective interaction of ligands with the receptor are discussed.