SYNTHESIS, PRELIMINARY EVALUATION AND MOLECULAR MODELING STUDIES OF NEW, CONFORMATIONALLY CONSTRAINED ANALOGS OF THE COMPETITIVE NMDA RECEPTOR ANTAGONIST 4-(PHOSPHONOMETHYL)-2-PIPERIDINECARBOXYLIC ACID (CGS-19755)

Two new spirobicyclophosphonate isomers (19 and 20), conformationally constrained analogues of the potent competitive NMDA antagonist CGS 19 755 (4), have been designed and synthetized with the aim of gaining in sight into the conformational preference of the crucial distal phospho nate moiety at the antagonist NMDA binding site. The preliminary biolo gical evaluation reveals that the activity as NMDA antagonist resides only in the (1R,5S,7R)-isomer (19), characterized by a (-)-gauche disp osition around the C1-C5 bond, thus confirming previously reported pha rmacophore models.