QUANTITATIVE-ANALYSIS OF THE STRUCTURAL REQUIREMENTS FOR BLOCKADE OF THE N-METHYL-D-ASPARTATE RECEPTOR AT THE PHENCYCLIDINE BINDING-SITE

Blockade of the N-methyl-D-aspartate receptor by uncompetitive antagon ists has implications for symptomatic and neuroprotective therapy of v arious neuropsychiatric diseases. Since the three-dimensional (3D) str ucture of this ion channel is unknown, the structural requirements for uncompetitive inhibition were investigated by application of a three- step strategy: At first, K-i values were measured for a number of stru cturally diverse compounds at the phencyclidine (PCP) binding site in postmortem human frontal cor tex. Second, a pharmacophore model was de veloped for this set of molecules employing a mathematical method call ed graph theory. The resulting pharmacophore provided a very good expl anation for the ability of structurally diverse compounds to bind to t he same binding site. Using the experimental data and the pharmacophor e as a basis for the third step, a three-dimensional quantitative stru cture-activity relationship (SD-QSAR) applying comparative molecular f ield analysis (CoMFA) was performed. The QSAR proved to be highly cons istent and showed good predictiveness for several additional molecules . The results give a deeper insight into the structural requirements f or effective NMDA receptor antagonism and offer the opportunity for im proved drug design. The study represents the first quantitative 3D-QSA R model for NMDA receptor blockade, and it comprises structurally very different molecules. That the alignment for a highly consistent CoMFA is based on an automated 3D pharmacophore analysis has important meth odological implications.