STRUCTURE-ACTIVITY-RELATIONSHIPS OF COMPETITIVE NMDA RECEPTOR ANTAGONISTS

The interaction of structurally constrained competitive NMDA receptor antagonists, (+/-)-cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), 2-amino-4,5-(1,2-cyclohexyl))-7-phosphonoheptanoic acid ( NPC 12626), phosphonomethyl-decahydroisoquinoline-3-carboxylic acid (L Y 274614), amino-5-phosphonomethyl[1,1'-biphenyl]-3-propanoic acid (SD Z EAB-515) and (S)-alpha-amino-5-phosphonomethyl[1,1':4',1 ''-terpheny l]-3-propanoic acid (SDZ 215-439), with their receptor was assessed us ing radioligand binding, protection against neurotoxicity in cortical neuronal cultures and computerised molecular modelling. All compounds inhibited the specific binding of [H-3]CGS 19755 and/or [H-3]CGP 39653 (inhibition constants 40-2000 nM), and protected neuronal cultures fr om NMDA-mediated injury (IC50 values 1.3-5.6 mu M). Quantitative confo rmational analyses indicated that the molecules fitted well to a NMDA receptor model. Our results draw attention to a deep hydrophobic pocke t, defined by the bi- and terphenyl containing antagonists (SDZ EAB-51 5, SDZ 215-439), which may influence potency and selectivity.