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J Med Chem. 2009 Aug 27;52(16):5093-107. doi: 10.1021/jm900363q.

Drug design, in vitro pharmacology, and structure-activity relationships of 3-acylamino-2-aminopropionic acid derivatives, a novel class of partial agonists at the glycine site on the N-methyl-D-aspartate (NMDA) receptor complex.

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Novartis Institutes for BioMedical Research, Neuroscience, 4056 Basel, Switzerland.


Retaining agonistic activity at the glycine coagonist site of the NMDA receptor in molecules derived from glycine or d-serine has proven to be difficult because in the vicinity of the alpha-amino acid group little substitution is tolerated. We have solved this problem by replacing the hydroxy group of d-serine with an amido group, thus keeping the hydrogen donor function and allowing for further substitution and exploration of the adjacent space. Heterocyclic substitutions resulted in a series of 3-acylamino-2-aminopropionic acid derivatives, with high affinities in a binding assay for the glycine site. In a functional assay assessing the activation of the glycine site, these compounds displayed a wide range of intrinsic efficacies, from antagonism to a high degree of partial agonism. Structure-activity relationships reveal that lipophilic substituents, presumably filling an additional hydrophobic pocket, are accepted by the glycine site, provided that they are separated from the alpha-amino acid group by a short linker.

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