| Autor: |
Bigge CF; Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105., Drummond JT, Johnson G, Malone T, Probert AW Jr, Marcoux FW, Coughenour LL, Brahce LJ |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 1989 Jul; Vol. 32 (7), pp. 1580-90. |
| DOI: |
10.1021/jm00127a030 |
| Abstrakt: |
To investigate the preferred spatial relationship of the distal phosphonic acid to the alpha-amino acid group of the established competitive N-methyl-D-aspartic acid (NMDA) antagonists APH (1) and APV (2), we have prepared a series of ortho-, meta-, and para-substituted (phosphonoalkyl)phenylglycine and -phenylalanine derivatives. With use of a [3H]CPP receptor binding assay, significant binding activity was observed to be critically dependent on both the position of substitution and length of alkyl spacing groups. Two compounds, 4-(phosphonomethyl)-phenylglycine (6, PD 129635) and 3-(phosphonomethyl)phenylalanine (15, PD 130527), displayed receptor-binding affinity comparable to that of APH. Like APH, these compounds were also effective in antagonizing both the proconvulsant and lethal action of NMDA-administered retrobulbar in the mouse. Data are also provided which compare directly the binding efficacy of these compounds against that disclosed recently for the related NMDA antagonist 18 (NPC 451). A preliminary comparison of the structures showing good receptor-binding affinity and in vivo antagonist activity suggests that the NMDA receptor prefers a "folded" rather than "extended" conformation. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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