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-M

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• 作者：Stephan Urwyler ; Philipp Floersheim ; Bernard L. Roy ; Manuel Koller
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：August 27, 2009
• 年：2009
• 卷：52
• 期：16
• 页码：5093-5107
• 全文大小：1177K
• 年卷期：v.52,no.16(August 27, 2009)
• ISSN：1520-4804

文摘

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 α-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 α-amino acid group by a short linker.