Synthesis and structure activity relationships of competitive NMDA antagonists with analgesic activity

Abstract: The compounds cis-3-(1-oxo-2-phosphonoethyl)-2-piperidinecarboxylic acid 1 and cis-3-(1-hydroxy-2-phosphonoethyl)-2-piperidinecarboxylic acid 2 were synthesized and found to be potent N-methyl-D-aspartate (NMDA) antagonists. NMR analysis showed that 1 prefers a 2eq,3ax chair conformation probably due to a conformer-stabilizing internal hydrogen bond. The active enantiomers (2R,3S)-3-(l-oxo-2-phosphonoethyl)-2-piperidinecarboxylic acid and (2R,3S,1'R)-3-(l-hydroxy-2-phosphonoethyl)-2-piperidinecarboxylic acid were synthesized and the NMDA receptor binding affinities (Ki values) were 64 and 74 nM, respectively.The analgesic effects of 1 and 2 were evaluated using the mouse hot-plate test and the mouse formalin model.A series of substituted (R)-α-amino-3-(phosphonomethyl)-2-quinolinepropanoic acids were synthesized. The active enantiomers were synthesized via a palladium-catalyzed coupling reaction of a 2-bromoquinoline derivative and a zinc reagent made from protected β-iodo-(R)-alanine. (R)-α-Amino-6,7-dimethyl-3-(phosphonomethyl)-2-quinolinepropanoic acid 3 exhibited a Ki value of 5 nM. A NiCl2(dppp)2-catalyzed coupling reaction with the zinc reagent made from [14C]-methyl iodide was used in the synthesis of radiolabeled 3.(R)-α-amino-3-(phosphonomethyl)-1,8-naphthyridine-2-propanoic acid, (R)-α-amino-3-(phosphonomethyl)-1,6-naphthyridine-2-propanoic acid and α-amino-3-(phosphonomethyl)-2-naphthalenepropanoic acid were synthesized. The structure activity relationships of the aryl- and heteroaryl-spaced NMDA antagonists revealed high receptor affinity for lipophilic substituents.