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.
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.
Urwyler
Stephan
S
Novartis Institutes for BioMedical Research, Neuroscience, 4056 Basel, Switzerland.
Floersheim
Philipp
P
Roy
Bernard L
BL
Koller
Manuel
M
D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002540:Cerebral Cortex / Q000378:metabolism; D015195:Drug Design; D054333:Drug Partial Agonism; D005998:Glycine / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D008958:Models, Molecular; D011869:Radioligand Assay; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D016194:Receptors, N-Methyl-D-Aspartate; D000409:Alanine; D005998:Glycine