Synthesis of a new series of N-hydroxy, N-alkylamides of aminoacids as ligands of NMDA glycine site

A new series of N-hydroxy, N-alkylamides of aminoacids structurally related to the N-hydroxy-S-amino-2 pyrrolidone [(+/-)HA-966] was synthesised and evaluated for the ability to displace [H-3]Glycine, [H-3]CGS 19755, [H-3]AMPA and [H-3]Kainate binding sites. The N-heptyl glycinamide 5a was the most potent compound (IC50 = 4.5 mu M) in inhibiting [H-3]Glycine binding. Compounds 5b, 5d, 5m, 5p, 5q and 5r showed an activity similar to (+/-)HA-966, whereas 5h, 5i, 5n and 5s appeared less active. None of the compounds tested exhibited a significant displacement of [H-3]AMPA and [H-3]Kainate binding sites. Compounds active in the [H-3]Glycine binding inhibited, to a different degree, NMDA induced contractions in guinea-pig LMPP preparation. (C) 1999 Editions scientifiques et medicales Elsevier SAS.