Cycloalkyl indole-2-carboxylates as useful tools for mapping the "North-Eastern" region of the glycine binding site associated with the NMDA receptor

A novel series of indole-2-carboxylate analogues of GV 150526 (1) in-which the terminal phenyl ring belonging to the side chain present in the positio n C-3 has been replaced with a bridged cycloalkyl group was synthesized and evaluated for its pharmacological profile. Modelling studies on this class of novel glycine antagonist allowed us to identify an asymmetric lipophili c pocket present in the "North-Eastern" region of the pharmacophoric model of the glycine binding site associated to the NMDA receptor. Among the deri vatives prepared, 3-[2-(1-adamantylaminocarbonyl)ethenyl]-4,6-dichloroindol e-2-carboxylic acid 6b and 3-[2(norbornylaminocarbonyl)ethenyl]-4,6-dichlor oindole-2-carboxylic acid 61 were found to be antagonists acting at the str ychnine-insensitive glycine binding site, showing nanomolar affinity for th e glycine binding site (K-i = 63 and 19 nM, respectively), coupled with hig h glutamate receptor selectivity (IC50 > 10(-5) M at the NMDA, AMPA, KA bin ding sites) and high in vivo potency after :systemic administration by inhi bition of convulsion induced by NMDA in mice.